CN103189074A

CN103189074A - Methods of treating rheumatoid arthritis using IL-17 antagonists

Info

Publication number: CN103189074A
Application number: CN2011800529537A
Authority: CN
Inventors: S·姆珀福; H·理查德斯; K·坦加维鲁; M·马哈切克
Original assignee: Novartis Vaccines and Diagnostics AG
Current assignee: Novartis Vaccines and Diagnostics AG
Priority date: 2010-11-05
Filing date: 2011-11-04
Publication date: 2013-07-03
Also published as: US20220193234A1; HRP20191162T1; TR201909531T4; JP2021104995A; CA3116725A1; CY1121802T1; US11534491B2; JP2023109910A; CL2013001213A1; JP6250109B2; EP2635303A2; KR20140008305A; SG189138A1; KR20180129991A; DK3111954T3; WO2012059598A2; IL282625A; KR20180019247A; JP2019142912A; MX362591B

Abstract

The disclosure relates to novel regimens for treating an inflammatory arthritis, e.g., rheumatoid arthritis (RA) patients, e.g., high risk RA patients, which employ a therapeutically effective amount of an IL-17 antagonist, e.g., 1L-1 7 binding molecule (e.g., IL-17 antibody or antigen binding fragment thereof, e.g., secukinumab) or IL-17 receptor binding molecule (e.g., IL- 17 antibody or antigen binding fragment thereof).

Description

Use the method for IL-17 antagonist for treating rheumatoid arthritis

The application advocates priority the 6114/0th, No. 533 to the U.S. Provisional Patent Application of submitting on November 5th, 2010, and whole disclosures of this U.S. Provisional Patent Application are all incorporated herein by reference.

Technical field

The application relates to the new method for the treatment of rheumatoid arthritis, and it utilizes the IL-17 binding molecule for the treatment of effective dose, for example IL-17 antibody, for example AIN457 antibody (being also referred to as " Su Jin monoclonal antibody (secukinumab) ").

Background technology

Rheumatoid arthritis (RA) is a kind of chronic, inflammatory, systemic autoimmune disease of source of disease the unknown.It is characterized in that symmetrical synovitis cause cartilage injury and destruction of joint and can concurrent multiple joint outside presentation.Owing to have autoantibody (for example rheumatoid factor (RF) and anti-citrulline protein antibodies (ACPA)), so RA is considered as autoimmune disease.RA is PD normally, observes functional status decline, remarkable sickness rate and too early mortality rate in the RA that has established.This disease can betide any age, and wherein the peak value sickness rate is between 30 years old and threescore.The target of long-term RA treatment is that disease is alleviated.

The moist medicine of amelioration of disease type wind resistance (DMARD) (according to purposes and traditional set that is classified as different reagent on the same group) is the first-line treatment for RA patient.DMARD is used for alleviating arthroncus and pain, minimizing acute stage labelling, limits the progress of joint injury and improves function of joint.DMARD (the most frequent is methotrexate (MTX)) is write out a prescription in medical diagnosis on disease (also namely, early stage RA) back, and this observes before aggressivity disease and the anamorphosis in the RA that has established usually.If pain and synovitis continue (especially if function is impaired), then begin the MTX therapy, and can add other DMARD (with or without steroid) to realize disease control.Unfortunately, only about 2/3 patient replys DMARD, and DMARD only partly controls the RA disease of having established.Even treating through DMARD among the RA patient of the clinical improvement that obtains alleviation or reach alleviation, the patient of 5-20% still continues to have the radiology progress.DMARD also has many ill effects (for example, hepatic injury, bone marrow depression and serious pulmonary infection) that limit its life-time service.

Owing to reply not enough and relevant with long-term DMARD treatment danger, introduced biological preparation and treated as two wires RA.Generally speaking, anti-TNF medicine

Be to reach the first batch of biological preparation of DMARD being replied not enough patient for DMARD treatment failure, and the RA that tnf inhibitor is frequent and MTX (or another DMARD) combination has been established with strong treatment.Unfortunately, 30% to 40% patient who suffers from the RA that has established is to the no response of TNF-alpha-2 antagonists and have patient's great majority of replying not reach at first to alleviate fully or lose in time and reply.Improved the inducing of resurrection to the short-term of long-term Biotherapeutics and the concern, particularly severe infections of long-term tolerance and safety (for example tuberculosis infection), liver toxicity, the cardiovascular disease of increase, the sheath patient's condition of emedullating (or aggravation) and since the sickness rate of the malignant tumor that TNF-α antagonism causes increase.M.Khraishi (2009) J.Rheumatol Suppl.82:25-32; People such as Salliot (2009) Ann.Rheum.Dis.68:25-32.Yet, usually continue to use tnf inhibitor invalid or produce adverse events until it, the biological agent that the clinicist can be exchanged into different tnf inhibitors or had different mechanism of action this moment is (for example,

[IL-1R antagonist],

[CD20 antagonist],

[CTLA4 fusion rotein] or

[IL-6 receptor antagonist]).People such as Scott (2010) The Lancet376:1095-1108.

Because the problems referred to above that current RA therapy exists need research and development to be used for RA patient's new therapy.

Summary of the invention

Su Jin monoclonal antibody (being in the newborn agent in the RA clinical development) is the anti-human antibodies of the complete human monoclonal of high-affinity that suppresses interleukin-17 A activity.In the research of the Proof of Concept (PoC) of RA, to the activity RA patient of the MTX that accepts consistent dose with increase single and subsequently 2 dosage (separately 21 days) use the Su Jin monoclonal antibody with 1mg/kg, 3mg/kg and 10mg/kg intravenous.People such as Hueber (2010) Sci.Transl.Med.2 (52): 52-72.Utilize the treatment of Su Jin monoclonal antibody to compare the clinical manifestation that can improve the RA among many patients fast with placebo.The neutralization of these digital proofs IL-17A may be effective to the RA patient who suffers from activity RA.Yet, be discrepant and expectation is avoided providing this medicine for the patient of drug resistance because the patient of Biotherapeutics is replied, our sought treatment method of RA, it differentiates that at first those most probables produce the favourable patient who replys to the antagonism of IL-17.Differentiated the RA patient subgroups of replying probability that the IL-17 antagonism is presented raising, described patient is named as " excessive risk RA patient ".

Therefore, the application's target provides the method for differentiating and treating " excessive risk RA patient ", it uses the IL-17 antagonist for the treatment of effective dose, for example IL-17 binding molecule (for example IL-17 antibody or its Fab, for example Su Jin monoclonal antibody) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab).

Another target of the application provides by determining whether the patient is that excessive risk RA patient determines that RA patient is to (for example utilizing the IL-17 antagonist, IL-17 binding molecule (for example IL-17 antibody or its Fab, for example Su Jin monoclonal antibody) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)) treatment produce the method for the probability reply.

Another target of the application provides the method for the treatment of inflammatory arthritis (for example AS, RA and PsA), the IL-17 antagonist of this method use treatment effective dose (for example, IL-17 binding molecule (for example IL-17 antibody or its Fab, for example, Su Jin monoclonal antibody) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)) during induction scheme and Concept of Maintenance, send this IL-7 antagonist by (for example) and provide to realize as the part of therapeutic scheme.

Therefore, herein disclosed is the method for the treatment of rheumatoid arthritis (RA), it comprises to the IL-17 antagonist of excessive risk RA patient administering therapeutic effective dose.

This paper also discloses the method for the treatment of rheumatoid arthritis (RA), and it comprises: be that excessive risk RA patient selects the patient that treats based on the patient a); And b) to the IL-17 antagonist of this patient's administering therapeutic effective dose.

Herein disclosed is the method for the treatment of rheumatoid arthritis (RA), it comprises: the following project of a) analyzing patient's sample: i, rheumatoid factor (RF), anti-citrulline protein antibodies (ACPA) or RF and ACPA; And ii, C-reactive protein (CRP), erythrosedimentation speed (ESR) or CRP and ESR the two; , if patient be RF+, ACPA+ or RF+ and ACPA+ and patient have high CRP level, high ESR or high CRP level and high ESR, then use the IL-17 antagonist to this patient and b) thereafter.

Herein disclosed is the method for the treatment of rheumatoid arthritis (RA), it comprises to the IL-17 antagonist of patient's administering therapeutic effective dose, and to be this patient be used for the treatment of through selecting based on following standard prerequisite: a) be RF+, ACPA+ or RF+ and ACPA+ the two; And b) have high CRP level, high ESR or high CRP level and high ESR the two.In some embodiments, step of applying comprises: a) use the IL-17 antagonist to the patient during induction scheme; And b) during Concept of Maintenance, uses the IL-17 antagonist to the patient thereafter.

Herein disclosed is the method for the treatment of rheumatoid arthritis (RA), it comprises: a) use the IL-17 antagonist of the dosage of three about 10mg/kg to excessive risk RA patient, each time in three dosage sent week about; And b) thereafter from sending a beginning in month after the 3rd intravenous dosages, used extremely about 150mg IL-17 antagonist of about 75mg to the patient in every month.

Herein disclosed is the scheme that is used for the treatment of rheumatoid arthritis (RA), it comprises: the patient who a) suffers from RA based on following Standard Selection: i, patient be RF+, ACPA+ or RF+ and ACPA+ the two; And ii, patient have high CRP level, high ESR or high CRP level and high ESR the two; And b) use the IL-17 antagonist of the dosage of three about 10mg/kg to this patient, first dosage is to send during the 0th week, and second dosage is to send during the 2nd week, and the 3rd dosage is to send during the 4th week; And c) begin during the 8th week thereafter, every month twice, every month, per two months or every three months are used extremely about 150mg IL-17 antagonist of about 75mg to the patient.

Herein disclosed is and determine that RA patient will produce the method for the probability of replying to the treatment that utilizes the IL-17 antagonist, it comprises the following project of analyzing patient's sample: a) rheumatoid factor (RF), anti-citrulline protein antibodies (ACPA) or RF and ACPA; And b) C-reactive protein (CRP), erythrosedimentation speed (ESR) or CRP and ESR the two, wherein have high CRP level, high ESR or high CRP level and high ESR if the patient is RF+, ACPA+ or RF+ and ACPA+ and patient, then this patient may reply the RA treatment that utilizes the IL-17 antagonist.

Herein disclosed is the IL-17 antagonist that is used for the treatment of rheumatoid arthritis (RA), it is characterized in that using the IL-17 antagonist to excessive risk RA patient.Herein disclosed is the IL-17 antagonist that is used for the treatment of rheumatoid arthritis (RA), it is characterized in that using the IL-17 antagonist to the patient, it is excessive risk RA patient and select to be treated that this patient is based on the patient.

Herein disclosed is the IL-17 antagonist that is used for the treatment of excessive risk RA patient.In some embodiments, excessive risk RA patient: a) be rheumatoid factor seropositivity (RF+), anti-citrulline protein antibodies seropositivity (ACPA+) or be RF+ and ACPA+ simultaneously; And b) have high C-reactive protein (CRP) level, high erythrosedimentation speed (ESR) or high CRP level and high ESR the two.In some embodiments, high CRP level is 〉=10mg/L, and is measured by hsCRP.In some embodiments, high ESR is 〉=28mm/h.

Herein disclosed is the IL-17 antagonist that is used for the treatment of rheumatoid arthritis (RA), it is characterized in that using the IL-17 antagonist to the patient, to be this patient be used for the treatment of through selecting based on following standard prerequisite: a) be RF+, ACPA+ or be RF+ and ACPA+ simultaneously; And b) have high CRP level, high ESR or high CRP level and high ESR the two.

Herein disclosed is the IL-17 antagonist that is used for the treatment of rheumatoid arthritis (RA), it is characterized in that the IL-17 antagonist: a) use at every turn all sending week about in three dosage with three dosage of about 10mg/kg to excessive risk RA patient; And b) thereafter from send after the 3rd intravenous dosages beginning in month every month with about 75mg extremely the dosage of about 150mg use to the patient.

Herein disclosed is the IL-17 antagonist that is used for the treatment of rheumatoid arthritis (RA), it is characterized in that: the following project of analyzing patient's sample: i, rheumatoid factor (RF), anti-citrulline protein antibodies (ACPA) or RF and ACPA; And ii, C-reactive protein (CRP), erythrosedimentation speed (ESR) or CRP and ESR the two; , if patient be RF+, ACPA+ or RF+ and ACPA+ and patient have high CRP level, high ESR or high CRP level and high ESR, then use the IL-17 antagonist to this patient and b) thereafter.

Herein disclosed is the IL-17 antagonist for the preparation of the purposes in the medicine for the treatment of RA, it is characterized in that using the IL-17 antagonist to excessive risk RA patient.

Herein disclosed is the IL-17 antagonist for the preparation of the purposes in the medicine for the treatment of RA, it is characterized in that at induction scheme and during Concept of Maintenance, use the IL-17 antagonist to excessive risk RA patient subsequently.

Herein disclosed is the pharmaceutical composition that is used for the treatment of RA, it comprises active ingredient IL-17 antagonist, wherein uses the IL-17 antagonist to excessive risk RA patient.

Herein disclosed is the pharmaceutical composition that is used for the treatment of RA, it comprises active ingredient IL-17 antagonist, wherein uses the IL-17 antagonist to excessive risk RA patient during induction scheme and Concept of Maintenance subsequently.

Herein disclosed is the therapeutic scheme that is used for the treatment of RA, it comprises: a) select excessive risk RA patient; B) during 0,2 and 4 weeks, use about 10mg/kg IL-17 antagonist to the patient; And c) uses extremely about 150mg IL-17 antagonist of about 75mg from the 8th week beginning every month to the patient thereafter.

Herein disclosed is treatment RA patient or excessive risk RA patient's method, it comprises: a) use the IL-17 binding molecule to the patient that these needs are arranged during induction scheme, this induction scheme provides the average maximal plasma concentration (C of the IL-17 binding molecule of about 360 μ g/ml _Max); And b) use the IL-17 binding molecule to the patient thereafter during Concept of Maintenance, this Concept of Maintenance provides: i) the average steady state valley concentration of the IL-17 binding molecule between about 8 μ g/ml and about 30 μ g/ml; And/or the ii) average A UC τ of about 331mg * day/L to the stable state of about 1323mg * day/L.

Herein disclosed is the IL-17 binding molecule that is used for the treatment of RA patient or excessive risk RA patient, it is characterized in that the IL-17 binding molecule: a) use to the patient during induction scheme, this induction scheme provides the average maximal plasma concentration (C of the IL-17 binding molecule of about 360 μ g/ml _Max); And b) use to the patient during Concept of Maintenance thereafter, this Concept of Maintenance provides: i) the average steady state valley concentration of the IL-17 binding molecule between about 8 μ g/ml and about 30 μ g/ml; And/or the ii) average A UC τ of about 331mg * day/L to the stable state of about 1323mg * day/L.

Herein disclosed is treatment excessive risk RA patient's method, it comprises: a) use the IL-17 binding molecule to the patient that these needs are arranged during induction scheme, this induction scheme provides the average maximal plasma concentration (C of the IL-17 binding molecule of about 401 μ g/ml _Max); And b) use the IL-17 binding molecule to the patient thereafter during Concept of Maintenance, this Concept of Maintenance provides: i) about 9.4 μ g/ml are to the average steady state valley concentration of the IL-17 binding molecule of about 31 μ g/ml; And/or the ii) average A UC τ of about 314mg * day/L to the stable state of about 1256mg * day/L.

Herein disclosed is and be used for the treatment of psoriasic IL-17 binding molecule, it is characterized in that the IL-17 binding molecule: a) use to the patient during induction scheme, this induction scheme provides the average maximal plasma concentration (C of the IL-17 binding molecule of about 401 μ g/ml _Max); And b) use to the patient during Concept of Maintenance thereafter, this Concept of Maintenance provides: i) about 9.4 μ g/ml are to the average steady state valley concentration of the IL-17 binding molecule of about 31 μ g/ml; And/or the ii) average A UC τ of about 314mg * day/L to the stable state of about 1256mg * day/L.

In some embodiments, Concept of Maintenance provides about 9.4 μ g/ml average steady state valley concentration to the IL-17 binding molecule of about 17.3 μ g/ml.In some embodiments, Concept of Maintenance provides the average steady state valley concentration of the IL-17 binding molecule of about 9.4 μ g/ml or about 17.3 μ g/ml.In some embodiments, induction scheme comprises week about intravenous and uses the IL-17 binding molecule.In some embodiments, Concept of Maintenance comprises every month subcutaneous administration IL-17 binding molecule.

Herein disclosed is test kit, it comprises: the pharmaceutical composition that comprises the IL-17 antagonist that a) is used for the treatment of patient's rheumatoid arthritis (RA); And b) describe description from this pharmaceutical composition to the patient that how use, wherein this patient is characterised in that: i) be RF+, ACPA+ or be RF+ and ACPA+ simultaneously; And ii) have high CRP level, high ESR or high CRP level and high ESR the two.

Herein disclosed is the IL-17 antagonist for the preparation of the purposes in the medicine for the treatment of RA, to be this patient be used for the treatment of through selecting based on following standard prerequisite: a) be RF+, ACPA+ or RF+ and ACPA+ the two; And b) have high CRP level, high ESR or high CRP level and high ESR the two.

Herein disclosed is the IL-17 antagonist for the preparation of the purposes in treatment patient's the medicine of RA, this patient is characterised in that: a) be RF+, ACPA+ or RF+ and ACPA+ the two; And b) have high CRP level, high ESR or high CRP level and high ESR the two, wherein this medicine through preparation comprising container, the IL-17 antagonist that each container all has a q.s with allow send per unit dosage at least about 75mg to about 150mg IL-17 antagonist.

Herein disclosed is the IL-17 antagonist for the preparation of the purposes in treatment patient's the medicine of RA, this patient is characterised in that: a) be RF+, ACPA+ or be RF+ and ACPA+ simultaneously; And b) have high CRP level, high ESR or high CRP level and high ESR the two, wherein to comprise container, each container all has the IL-17 antagonist of q.s and sends per unit dosage at least about 10mg/kg to allow this medicine through preparation.

Herein disclosed is the IL-17 antagonist for the preparation of the purposes in treatment patient's the medicine of RA, this patient is characterised in that: a) be RF+, ACPA+ or RF+ and ACPA+ the two; And b) have high CRP level, high ESR or high CRP level and high ESR the two, wherein allow that with per unit dosage intravenous sends the dosage of about 10mg/kg and prepare this medicine.

Herein disclosed is the IL-17 antagonist for the preparation of the purposes in treatment patient's the medicine of RA, this patient is characterised in that: a) be RF+, ACPA+ or RF+ and ACPA+ the two; And b) have high CRP level, high ESR or high CRP level and high ESR the two, wherein with per unit dosage allow the about 75mg/kg of subcutaneous delivery extremely the dosage of about 150mg IL-17 antagonist prepare this medicine.

Herein disclosed is the patient's who selects to treat RA testing in vitro method: it comprises definite: i, patient whether be RF+, ACPA+ or RF+ and ACPA+ the two; And ii, patient whether have high CRP level, high ESR or high CRP level and high ESR the two.In some embodiments of disclosed testing in vitro method, the patient has improved treatment to following scheme and replys: IL-17 antagonist from the dosage of three about 10mg/kg to this patient that a) use, first dosage is to send during the 0th week, second dosage is to send during the 2nd week, and the 3rd dosage is to send during the 4th week; And b) begin during the 8th week thereafter, every month twice, every month, per two months or every three months are used about 75mg to about 150mg IL-17 antagonist to the patient.

But herein disclosed is the method that the patient who suffers from RA is produced the information of transmission form, it comprises: the following project of a) analyzing patient's sample: i) rheumatoid factor (RF), anti-citrulline protein antibodies (ACPA) or RF and ACPA; And ii) C-reactive protein (CRP), erythrosedimentation speed (ESR) or CRP and ESR the two; And b) but the result of step a) is converted to the information of transmission form.

This paper also provides the method for the treatment of inflammatory arthritis, it comprises to (for example suffering from inductive dose that the patient who is selected from following inflammatory arthritis uses three about 10mg/kg, the intravenous inductive dose) or some (for example, 1,2,3,4 or 5) the IL-17 antagonist of the inductive dose of about 150mg (for example subcutaneous inductive dose), for example IL-17 binding molecule (for example IL-17 antibody or its Fab, for example Su Jin monoclonal antibody) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab): rheumatoid arthritis (RA), spondyloarthropathy, ankylosing spondylitis (spondylarthritis)) and arthritic psoriasis.In some embodiments, send inductive dose week about, and (for example about 75mg is to about 150mg to about 300mg to begin to use about 75mg to the patient in every month from next month of sending of (for example) final inductive dose thereafter, for example about 75mg or about 150mg) maintenance dose (for example, subcutaneous maintenance dose) of IL-17 antagonist (for example Su Jin monoclonal antibody).

This paper also provides the method for the treatment of RA, it comprises the patient who selects RA patient (for example excessive risk RA patient) or have the baseline CRP level of rising, week about (for example, the 0th, during 2 and 4 weeks) (for example use about 10mg/kg to this patient, via intravenous route) the IL-17 antagonist is (for example, IL-17 binding molecule (for example IL-17 antibody or its Fab, Su Jin monoclonal antibody for example) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)), (for example reach every month thereafter, from the beginning of the 8th week) (for example about 75mg is to about 150mg to about 300mg to use about 75mg to this patient, for example about 75mg or about 150mg) (for example, passing through subcutaneous route) IL-17 antagonist.

In some embodiments of disclosed method, test kit, purposes, pharmaceutical composition and scheme, excessive risk RA patient: be rheumatoid factor seropositivity (RF+), anti-citrulline protein antibodies seropositivity (ACPA+), or be RF+ and ACPA+ simultaneously a); And b) have high C-reactive protein (CRP) level, high erythrosedimentation speed (ESR) or high CRP level and high ESR the two.

In some embodiments of disclosed method, test kit, purposes, pharmaceutical composition and scheme, the IL-17 antagonist is IL-17 binding molecule or IL-17 receptors bind molecule.In some embodiments, IL-17 binding molecule or IL-17 receptors bind molecule are to be selected from following IL-17 binding molecule (for example IL-17 antibody): a) Su Jin monoclonal antibody; B) in conjunction with the IL-17 antibody of the epi-position of IL-17, this epi-position comprises Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129; C) in conjunction with the IL-17 antibody of the epi-position of IL-17, this epi-position comprises Tyr43, Tyr44, Arg46, Ala79, Asp80; D) in conjunction with the IL-17 antibody of epi-position of the IL-17 homodimer with two ripe IL-17 protein chains, this epi-position comprises Tyr43, Tyr44, Arg46, Ala79, an Asp80 on Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 and another chain on the chain; E) in conjunction with the IL-17 antibody of epi-position of the IL-17 homodimer with two ripe IL-17 protein chains, this epi-position comprises Tyr43, Tyr44, Arg46, Ala79, the Asp80 on Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 and another chain on the chain, the wherein K of IL-17 binding molecule _DBe about 100pM to 200pM, and wherein the interior half-life of body of IL-17 binding molecule is about 4 weeks; And f) comprises the IL-17 antibody that is selected from following antibody: the immunoglobulin heavy chain variable domain (V that i) comprises the aminoacid sequence shown in the SEQ ID NO:8 _H); Immunoglobulin light chain variable domain (the V that ii) comprises the aminoacid sequence shown in the SEQ ID NO:10 _L); The immunoglobulin V that iii) comprises the aminoacid sequence shown in the SEQ ID NO:8 _HDomain and comprise the immunoglobulin V of the aminoacid sequence shown in the SEQ ID NO:10 _LDomain; The immunoglobulin V that iv) comprises the hypervariable region shown in SEQ ID NO:1, SEQ ID NO:2 and the SEQ ID NO:3 _HDomain; The immunoglobulin V that v) comprises the hypervariable region shown in SEQ ID NO:4, SEQ IDNO:5 and the SEQ ID NO:6 _LDomain; The immunoglobulin V that vi) comprises the hypervariable region shown in SEQ ID NO:11, SEQ ID NO:12 and the SEQ ID NO:13 _HDomain; The immunoglobulin V that vii) comprises the hypervariable region shown in SEQID NO:1, SEQ ID NO:2 and the SEQ ID NO:3 _HDomain and comprise SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 shown in the immunoglobulin V of hypervariable region _LDomain; Reach the immunoglobulin V that viii) comprises the hypervariable region shown in SEQ ID NO:11, SEQ ID NO:12 and the SEQ ID NO:13 _HDomain and comprise SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 shown in the immunoglobulin V of hypervariable region _LDomain.

In the preferred embodiment of disclosed method, test kit, purposes, pharmaceutical composition and scheme, the IL-17 binding molecule is human antibodies.In embodiment disclosed method, test kit, purposes, pharmaceutical composition and scheme even preferred, the IL-17 binding molecule is the Su Jin monoclonal antibody.

Brief Description Of Drawings

Fig. 1 shows the research design of CAIN457F2201 research.

Fig. 2: A is presented in the complete analysis collection (FAS) in research CAIN457F2201 the last observation of replying until the ACR20 of the treatment in the 16th week carry down (LOCF); B shows among the excessive risk RA patient that the ACR20 until the treatment in the 16th week replys (LOCF); C shows among the FAS that respondent (R) and nonresponder (NR) reply to the 52nd week ACR20 in time.

The ACR50 that Fig. 3: A is presented in the complete analysis collection (FAS) in research CAIN457F2201 until the treatment in the 16th week replys (LOCF); B shows among the FAS that respondent (R) and nonresponder (NR) reply to the 52nd week ACR50 in time.

The ACR70 that Fig. 4: A is presented in the complete analysis collection (FAS) in research CAIN457F2201 until the treatment in the 16th week replys (LOCF); B shows among the FAS that respondent (R) and nonresponder (NR) reply to the 52nd week ACR70 in time.

Fig. 5: A shows among the research CAIN457F2201FAS that the DAS28-CRP with respect to baseline until the treatment in the 16th week changes (LOCF); B is presented at respondent among the FAS (R) and nonresponder (NR) and replys to the 52nd week DAS28-CRP in time.

Fig. 6: A show among the research CAIN457F2201FAS until the treatment in the 16th week with respect to baseline

Scoring changes (LOCF); B show respondent (R) and nonresponder (NR) among the FAS to the 52nd week in time

Reply.

Fig. 7 shows that respondent's (R) and nonresponder (NR) ACR20/50/70 replys among the 52nd when week FAS.

ACR20/50/70 when Fig. 8: A showed for the 16th week among excessive risk RA patient and the non-excessive risk RA patient replys %.DAS28-CRP when B showed for the 16th week among excessive risk RA patient and the non-excessive risk RA patient replys.

Fig. 9 is presented in the CAIN457F2201 research, according to the ACR20 respondent ratio of dosage group and CRP baseline values.From left to right, post represents all patients, CRP baseline respectively greater than the patient of 10mg/L, greater than the patient of 20mg/L and greater than the patient of 30mg/L.

Figure 10 shows the simulation Su Jin monoclonal antibody medicine kinetics (PK) in the patient with rheumatoid arthritis.The PK that induces strategy (dosage of a 300mg of subcutaneous administration when the 0th week) is not used in the solid line demonstration, dotted line shows the subcutaneous PK that induces strategy (subcutaneous administration 300mg when the 0th, 1,2,3 and 4 weeks) of use, and the dotted line demonstration uses intravenous to induce the PK of strategy (intravenous is used 10mg/kg when the 0th, 2 and 4 weeks).These three selections separately all after carry out the subcutaneous 300mg of using of per 4 weeks and be used for keeping.

Detailed description of the invention

The 1987 Americanism damp disease association of RA (American College of Rheumatology) (ACR) the criteria for classification patient that will suffer from the RA that has established are distinguished mutually with the individuality of the combination with other clear and definite rheumatology diagnosis.Described standard is helpless to differentiate the patient who suffers from early stage RA disease, and described patient may benefit from early intervention.2010, ACR provided new categorizing system, the RA feature (hereinafter being " 2010ACR/EULAR " standard) of the disease commitment of its concern and persistence and/or aggressivity disease association connection.People such as Aletaha (2010) Ann.Rheum.Dis.69:1580-1588.The 2010ACR/EULAR categorizing system is paid close attention to six standards; Preceding two standards define should carry out the people that RA detects, and remains four standards by mark (table 1).Scoring be 6 or bigger value indicate clear and definite RA.

* this standard mesh is to emerging patient's classification.In addition, having the patient who formerly meets that the typical aggressivity disease of rheumatoid arthritis and medical history satisfy 2010 standards should be classified as and suffer from RA.Suffer from prolonged sickness (comprising the disease that is in non-active phase (through treatment or untreated)) and should be categorized as based on the patient that the data that retrospective obtains have met standard in 2010 before this and suffer from RA.

Patient diagnosis with different manifestations is also different, but can comprise such as patient's condition such as systemic lupus erythematosus, arthritic psoriasis and gouts.If the unclear differential diagnosis that should consider which is correlated with should be seeked advice from the rheumatology expert.

Suffer from RA although the patient of scoring＜6/10 can not be classified as, can estimate again its state, and as time passes may conformance with standard.

Any swelling or the tenderness joint found when the § joint involvement refers to have a medical check-up, it can confirm by the imaging evidence of synovitis.In assessment, except long-range interphalangeal joint, first wrist palm and first metatarsophalangeal joints.According to the position in the joint of getting involved and quantity the classification that the joint distributes is classified, put under in the highest possible classification based on the pattern of joint involvement.

" big joint " refers to shoulder, elbow, hip, knee joint and ankle.

# " little joint " refers to metacarpophalangeal joints, proximal interphalangeal joint, second to the 5th metatarsophalangeal joints, thumb interphalangeal joint and carpal joint.

* is in this classification, and at least one joint of getting involved is necessary for little joint; Other joints can comprise arbitrary combination in big joint and other little joints, and the joint (for example temporomandibular joint, acromion clavicle, breast clavicle etc.) of not listing especially, other other places.

Feminine gender refers to be less than or equal to the upper limit (ULN) of the normal value of laboratory and analysis; The low positive refers to that the IU value is higher than the ULN of laboratory and analysis, but＜/=3 times of ULN; The high positive refers to the IU value〉3 times of the ULN of laboratory and analysis.If only can obtain being expressed as rheumatoid factor (RF) information of positive or negative, then positive findings should be chosen as the low positive of RF.The anti-citrulline protein antibodies of ACPA=.

Be defined as normal/abnormal by local laboratory standard.The CRP=C-reactive protein; ESR=erythrosedimentation speed.

When § § duration of symptoms referred to assess, whether the persistent period of the clinical articular synovitis S or S that relates to (for example pain, swelling, tenderness) of patient oneself report was no matter be therapeutic state.

Seeking RA patient to IL-17 binding molecule (IL-17 antibody for example, Su Jin monoclonal antibody for example) during the predictability index of replying for the treatment of, but we two of having analyzed in four standards of grading of 2010ACR/EULAR determine whether described standard can influence replying that IL-17 binding molecule (for example Su Jin monoclonal antibody) is treated.At first, analyze the patients serum and learn to determine whether the patient is RF+ and/or ACPA+.Secondly, analyze the existence of acute phase reactant to determine whether the patient has high C-reactive protein (CRP) level and/or high erythrosedimentation speed (ESR).In the method, finding that following patient more may have well the treatment of IL-17 binding molecule (for example IL-17 antibody, for example Su Jin monoclonal antibody) replys: 1) be RF+ or ACPA+ (or the two); And 2) have high CRP level or ESR (or the two).Described patient (being called " excessive risk RA patient " herein) is those marked feature persons with RA.(referring to, for example, people such as Yildirim, (2004) Annals Clin.Lab.Sci34:423).Therefore, herein disclosed is the method for the treatment of rheumatoid arthritis (RA), it comprises to the IL-17 binding molecule of excessive risk RA patient administering therapeutic effective dose.

In addition, our baseline CRP level of determine having raise (for example,〉about 10mg/L) is also with relevant to replying of Su Jin monoclonal antibody.Therefore, herein disclosed is the method for the treatment of rheumatoid arthritis (RA), it comprises to the IL-17 binding molecule of RA patient's administering therapeutic effective dose of the baseline CRP level that presents rising (for example, greater than about 10mg/L, greater than about 20mg/L, greater than about 30mg/L).

We find that further the therapeutic scheme that is used for the treatment of excessive risk RA patient also can be used for treating the RA of non-high-risk patient and has the patient of other inflammatory arthritis (for example ankylosing spondylitis (AS) or arthritic psoriasis (PsA)).Therefore, herein disclosed is the administration and the therapeutic scheme that solve inflammatory arthritis (for example RA, AS, PsA), it comprises to the IL-17 binding molecule of patient's administering therapeutic effective dose of suffering from inflammatory arthritis.

Term " comprise " contain " comprising " and " by ... form ", for example, the compositions of " comprising " X can only be made up of maybe X can comprise other things, for example X+Y.

Unless context is indicated in addition, otherwise the term " about " relevant with numerical value x mean+/-10%.Term " about " is at pharmacokinetics (PK) parameter (for example, AUC, C _Max, t _Max, valley level etc.) when using, refer to that those skilled in the art can think that it is bioequivalent that treatment (for example, dosage and/or dosage regimen) is treated with contrast.For bioequivalence, the standard method that shows bioequivalence will prove given PK parameter between two treatments (i.e. contrast treatment and test are treated) (for example AUC, C statistically _Max) ratio between 0.8 and 1.25, it shows (lower limit of this CI is higher than 0.8, and the upper limit of this CI is lower than 1.25) by near 90% confidence interval (CI) this ratio.Therefore, for example, obtain the contrast C of 10 μ g/ml as if the experimental session for the treatment of and test the PK curve for the treatment of in comparative control _Max, then treatment is bioequivalent if those skilled in the art think test, then will test treatment and be considered as " about 10 μ g/ml ".As used herein, the pharmacokinetics technics is t for example _Max, t _1/2, AUC, AUC _(0-τ)(AUC when finishing to the given administration period hereinafter is " AUC τ "), C _MaxHas the implication that this area is accepted.

The term administering relevant with chemical compound (for example moist medicine of IL-17 binding molecule or wind resistance) " be used in reference to by arbitrary approach and send chemical compound.

Phrase " activity rheumatoid arthritis " or " activity RA " are used for meaning and have visible sign and symptom the RA of (for example, swelling, be difficult to bending etc.).

The behavior that term " analysis " is used in reference to detection, discriminating, screening or determines, the behavior can implement by arbitrary usual manner.Whether the existence of specific markers that for example, can be by using analysis samples such as elisa assay, Northern blot, imaging is to exist labelling in the test sample.

Term " basically " is not got rid of " fully ", and for example, the compositions of " being substantially free of " Y can not contain Y fully.If need, word " basically " can omit from the application's definition.

" mg/kg " used herein refers to that mg medicine/kg is applied the weight in patients of medicine.

" IL-17 antagonist " used herein refers to can antagonism (for example, reduce, suppress, reduce, block, postpone) IL-17 function, the molecule of expression and/or signal transduction (for example, by blocking-up IL-17 and IL-17 receptors bind).The limiting examples of IL-17 antagonist comprises IL-17 binding molecule and IL-17 receptors bind molecule.In some embodiments of disclosed method, scheme, test kit, process, purposes and compositions, adopt the IL-17 antagonist.

" IL-17 binding molecule " refers to separately or to unite any molecule that other molecules are combined with human IL-17 antigen.Can show association reaction by standard method (qualitative analysis), described method comprises that (for example) is for binding analysis, competition analysis or the bioanalysis determined the inhibition of IL-17 and its receptors bind, or the binding analysis of arbitrary kind, use the negative control test of antibody (for example anti-CD 25 antibody) have uncorrelated specificity but to have an identical isotype as reference.The antibody that the limiting examples of IL-17 binding molecule comprises micromolecule, IL-17 receptor bait and the antibody that produced by B cell or hybridoma and chimeric antibody, CDR transplant or human antibodies or its any fragment (F (ab') for example ₂Reach the Fab fragment) and strand or single structure domain antibodies.Preferably, IL-17 binding molecule antagonism (for example reduce, suppress, reduce, block, postpone) IL-17 function, expression and/or signal transduction.In some embodiments of disclosed method, scheme, test kit, process, purposes and compositions, adopt the IL-17 binding molecule.

" IL-17 receptors bind molecule " means can be separately or unite arbitrary molecule of other molecules and human IL-17 receptors bind.Can show association reaction by standard method (qualitative analysis), described method comprises that (for example) is for binding analysis, competition analysis or the bioanalysis of the inhibition of determining the IL-17 receptor is combined with IL-17, or the binding analysis of arbitrary kind, use the negative control test of antibody (for example anti-CD 25 antibody) have uncorrelated specificity but to have an identical isotype as reference.The limiting examples of IL-17 receptors bind molecule comprises micromolecule, IL-17 receptor bait and produces the antibody transplanted at the antibody of IL-17 receptor and chimeric antibody, CDR or human antibodies or its any fragment (F (ab') for example by B cell or hybridoma ₂Reach the Fab fragment) and strand or single structure domain antibodies.Preferably, IL-17 receptors bind molecule antagonism (for example reduce, suppress, reduce, block, postpone) IL-17 function, expression and/or signal transduction.In some embodiments of disclosed method, scheme, test kit, process, purposes and compositions, adopt IL-17 receptors bind molecule.

Term used herein " antibody " comprises whole antibody and any antigen-binding portion thereof or strand.Natural antibody is to comprise by at least two weights (H) chain of disulfide bond interconnection and the glycoprotein of two light (L) chains.Each heavy chain comprises variable region of heavy chain, and (this paper is abbreviated as V _H) and CH.CH comprises three domain: CH1, CH2 and CH2.Each light chain comprises variable region of light chain, and (this paper is abbreviated as V _L) and constant region of light chain.Constant region of light chain comprises a domain C L.Can be with V _HAnd V _LThe district further is subdivided into hypervariable region (being called complementary determining region (CDR)) and comparatively conservative district's (being called framework region (FR)), and the two is mixed with arrangement.Each V _HAnd V _LBe made of three CDR and four FR, it is arranged in the following order from aminoterminal to c-terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.The binding structural domain with AI is contained in the variable region of heavy chain and light chain.The constant region of antibody can mediate the combination of immunoglobulin and host tissue or the factor (first component (Clq) that comprises immune various cell (for example effector lymphocyte) and classical complement system).In some embodiments of disclosed method, scheme, test kit, process, purposes and compositions, adopt the antibody at IL-17 or IL-17 receptor.

" antigen-binding portion thereof " of term antibody used herein refers to keep specificity to be bonded to antigen (for example, the antibody fragment of ability IL-17).Show that the antigen combined function of antibody can be realized by the fragment of full length antibody.The example of the binding fragment that " antigen-binding portion thereof " of term antibody contains comprises the Fab fragment, also namely by V _L, V _H, the unit price fragment formed of CL and CH1 domain; F (ab') ₂Fragment also namely comprises two in the bivalence fragment of hinge region by the Fab fragment of disulfide bridge bond connection; By V _HAnd the Fd fragment of CH1 domain composition; V by the antibody single armed _LAnd V _HThe Fv fragment that domain is formed; DAb fragment (people such as Ward, (1989) Nature341:544-546), it is by V _HDomain is formed; And the complementary determining region (CDR) that separates.Exemplary antigen binding site comprises the CDR of Su Jin monoclonal antibody, as shown in SEQ ID NO:1-6 and 11-13 (table 4), is preferably heavy chain CDR3.In addition, although two domain (V of Fv fragment _LAnd V _H) be by independent gene code, but can utilize recombination method, by synthetic connexon these two domains are combined, make these two domains can become single protein chain, wherein V _LAnd V _HThe zone pairing forms monovalent molecule and (is called strand Fv (scFv); For example, referring to people such as Bird, 1988Science242:423-426; Reach people such as Huston, 1988Proc.Natl.Acad.Sci.85:5879-5883).Described single-chain antibody is also intended to be encompassed in the term " antibody ".Use the known routine techniques of those skilled in the art to obtain single-chain antibody and antigen-binding portion thereof.In some embodiments of disclosed method, scheme, test kit, process, purposes and compositions, adopt single-chain antibody or at antigen-binding portion thereof or the IL-17 receptor of the antibody (for example Su Jin monoclonal antibody) of IL-17.

Term " pharmaceutically acceptable " means the not avirulence material of the bioactive effectiveness of interferon activity composition.

" isolated antibody " used herein refers to be substantially free of the antibody (for example, specificity is substantially free of specificity in conjunction with the antibody of the antigen beyond the IL-17 in conjunction with the isolated antibody of IL-17) of other antibody with different antigenic specificities.Isolated antibody can be substantially free of other cell materials and/or chemicals.Yet, the isolated antibody of " specificity in conjunction with " IL-17 can with other antigens (for example IL-17 molecule of other species) cross reaction.In some embodiments of disclosed method, scheme, test kit, process, purposes and compositions, the IL-17 antagonist is isolated antibody.

Term used herein " monoclonal antibody " or " monoclonal antibody combination " refer to have single molecular antibody molecule preparation.Monoclonal antibody combination presents single binding specificity and affinity for defined epitope.In some embodiments of disclosed method, scheme, test kit, process, purposes and compositions, the IL-17 antagonist is monoclonal antibody.

Term used herein " human antibodies " is intended to comprise the antibody with variable region, in middle frame district, described variable region and the CDR district the two all derived from the sequence in mankind source.In addition, if antibody contains constant region, then this constant region is also derived from described human sequence, for example human the kind is that sequence or human the kind are that the antibody of the mutant form of sequence or the total framework sequence that contains derived from human class framework sequence analysis is (as people such as Knappik, (2000.J Mol Biol296 is described in the 57-86)." human antibodies " needn't be produced by the mankind, human tissue or human cell.The application's human antibodies can comprise not being by human sequence's amino acids coding residue (for example, by external random mutagenesis or direct mutagenesis or the sudden change introduced by somatic mutation in the body).Yet term used herein " human antibodies " does not desire to comprise that the CDR sequence that is derived from another mammal (for example mice) kind has migrated to the antibody on people's class framework sequence.In some embodiments of disclosed method, scheme, test kit, process, purposes and compositions, the IL-17 antagonist is human antibodies.

Term " IL-17 " refers to IL-17A (being called CTLA8 before this), and comprises from the polymorph variant of wild type IL-17A, the IL-17A of different plant species (for example, human, mice and monkey) and the function equivalent of IL-17A.The whole sequence identity of the function equivalent of IL-17A of the present invention and wild type IL-17A (for example human IL-17A) be preferably at least about 65%, 75%, 85%, 95%, 96%, 97%, 98% or even 99%, and keep basically inducing the ability that produces IL-6 by human corium fibroblast.

Term " K _D" meaning dissociation constant, it is available from K _dWith K _aRatio (be K _d/ K _a), and represent with molar concentration (M).Can use the ripe method of setting up in this area to measure the K of antibody _DValue.Measure the K of antibody _DMethod use surface plasma body resonant vibration or (for example use bio-sensor system

System).In some embodiments of the present invention, (for example IL-17 binding molecule (for example IL-17 antibody or its Fab, for example Su Jin monoclonal antibody) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab) are with the K of about 100pM to 250pM for the IL-17 antagonist _DIn conjunction with human IL-17.

Term used herein " affinity " refers to the interaction strength between single antigenic site place's antibody and the antigen.In each antigenic site, the variable region of antibody " arm " by weak noncovalent force at a plurality of site and AI; It is more big to interact, and then affinity is more strong.Known in the art for assessment of the standard analytical process of antibody to the affinity of the IL-17 of different plant species, comprise (for example) ELISA, western blot and RIA.Also can be by the binding kinetics (for example, binding affinity) of standard analytical process known in the art (for example by the Biacore analytic process) assessment antibody.Describe in further detail among the embodiment for assessment of the effect Analysis method of antibody to the functional character of IL-17 (for example, receptors bind, prevent or improve osteolysis).

Term used herein " individuality " reaches " patient " and comprises any mankind or non-human animal.Term " non-human animal " comprises all vertebratess, for example mammal and nonmammalian, for example non-human primate, sheep, Canis familiaris L., cat, horse, cattle, chicken, Amphibian, reptile class etc.

Should understand, relate to respect to the remarkable reduction on the statistics that does not have under the antibody situation when specific control antibodies (or exist uncorrelated) observed given activity as the antibody of measuring " inhibition " one or more IL-17 functional character (for example, biochemistry, immunochemistry, cell, physiology or other biological activity or like that) according to method known in the art and that describe in this article.The antibody that suppresses the IL-17 activity significantly reduces measured parameter statistically, for example, reduces at least 10%, at least 50%, 80% or 90%, and in certain embodiments, the application's antibody can suppress to surpass 95%, 98% or 99% IL-17 functional activity.

Except as otherwise noted, otherwise term " derivant " (for example is used for definition IL-17 antagonist of the present invention, IL-17 binding molecule (for example IL-17 antibody or its Fab, for example Su Jin monoclonal antibody) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)) aminoacid sequence variant and the covalent modification of (for example particular sequence)." functional deriv " comprise with disclosed IL-17 antagonist (for example, IL-17 binding molecule (for example IL-17 antibody or its Fab, for example Su Jin monoclonal antibody) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)) have a common qualitative bioactive molecule.Functional deriv has comprised fragment and the peptide analogues of IL-17 antagonist disclosed herein.Fragment is included in the interior zone of sequence of polypeptide of the present invention (for example particular sequence).The functional deriv of IL-17 antagonist disclosed herein preferably comprises V _HAnd/or V _LDomain, the V of described domain and IL-17 binding molecule disclosed herein _HAnd/or V _LSequence (for example, the V of table 4 _HAnd/or V _LSequence) whole sequence identity be at least about 65%, 75%, 85%, 95%, 96%, 97%, 98% or even 99%; Or comprise CDR, the whole sequence identity of the CDR (for example, having 1,2 or 3 aminoacid difference with CDR described in the table 4) of described CDR and disclosed herein IL-17 antagonist (for example Su Jin monoclonal antibody) be at least about 65%, 75%, 85%, 95%, 96%, 97%, 98% or even 99%; And keep basically suppressing the ability that the IL-6 of the human corium fibroblast that IL-17 induces produces in conjunction with human IL-17 or (for example).

" suppressing IL-16 " used herein refers to that IL-17 antagonist (for example Su Jin monoclonal antibody) reduces the ability from human corium fibroblast generation of former generation IL-6.IL-17 (people such as Hwang SY, (2004) Arthritis Res Ther are depended in the generation of IL-6 in the former generation mankind (corium) fibroblast; 6:R120-128).In brief, in the presence of the IL-17 binding molecule with Fc part of variable concentrations or human IL-17 receptor with the IL-17 stimulating human corium fibroblast of recombinating.Chimeric anti-CD 25 antibody

(basiliximab) can be easily used as negative control.After stimulating 16h, get supernatant and pass through elisa assay IL-6.As above-mentioned test, when namely producing to measure this inhibition activity about the IL-6 that is induced by the hu-IL-17 in the human corium fibroblast, IL-17 antagonist disclosed herein (for example, IL-17 binding molecule (for example IL-17 antibody or its Fab, Su Jin monoclonal antibody for example) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)) the inhibition IL-6 that has about 50nM or littler (for example, about 0.01nM is to about 50nM) usually produces the IC of (in the presence of 1nM mankind IL-17) ₅₀In some embodiments of disclosed method, scheme, test kit, process, purposes and compositions, the IL-17 antagonist (for example, IL-17 binding molecule (for example IL-17 antibody or its Fab, for example Su Jin monoclonal antibody) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab) and functional deriv thereof suppress the IC that IL-6 produces as hereinbefore defined ₅₀Be about 20nM or littler, more preferably from about 10nM or littler, more preferably from about 5nM or littler, more preferably from about 2nM or littler, 1nM or littler more preferably from about.

Term " covalent modification " comprise with organic protein or nonprotein derivating agent to the modification of the polypeptide of the present invention that for example has particular sequence or its fragment, with fusion and the post translational modification of allogeneic polypeptide sequence.For example have particular sequence through the polypeptide of covalent modification still can be by the human IL-17 of crosslinked combination or the IL-6 that for example suppresses the human dermal fibroblast that IL-17 induces produce.Traditionally, the amino acid residue by making targeting with can with organic derivating agent reaction of selected side or terminal residue reaction, or by utilizing the post translational modification mechanism that in selected recombinant host cell, works, introduce covalent modification.Some post translational modification is the result that recombinant host cell acts on expressed polypeptide.Glutaminyl and asparaginyl-residue go amide to turn to corresponding glutamyl and aspartyl residue after being everlasting and translating.Perhaps, under appropriate acid condition, these residues are deaminized.Other post translational modifications comprise the hydroxylating of proline and lysine; The hydroxyl phosphorylation of seryl-, tyrosine or Threonyl residue; Lysine, arginine and the alpha-amino of histidine side chain methylate, referring to for example T.E.Creighton, and Proteins:Structure and Molecular Properties, W.H.Freeman﹠amp; Co., San Francisco, 79-86 page or leaf (1983).Covalent modification for example comprises: comprise the polypeptide of the present invention that for example has particular sequence and the fusion rotein of aminoacid sequence variant (such as immunoadhesin (immunoadhesin)) thereof, and with the N-end fusions of allos signal sequence.

Phrase " basically consistent " means related amino acid or nucleotide sequence (for example CDR, V _HOr V _LThe territory) consistent with specific reference sequences or compare with specific reference sequences and to have unsubstantiality difference (for example substituting via conserved amino acid).Unsubstantiality difference comprises that small aminoacid changes, and substitutes such as carry out 1 or 2 in 5 amino acid whose sequences having of appointed area.Under the situation of antibody, the antibody that takes place to substitute has the phase homospecificity and has at least 50% of identical affinity.With sequence disclosed herein basically the sequence of consistent (for example at least about 85% sequence identity) also be the application's a part.In some embodiments, sequence identity can be about 90% or more than, for example 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more than.

" concordance " about natural polypeptides and its functional derivatives is defined as in this article, with sequence alignment and introduce the gap in case of necessity to realize maximum concordance percentage ratio, and do not consider that any conservative is replaced by after the sequence identity part percentage ratio of the amino acid residue identical with the residue of corresponding natural polypeptides in the candidate sequence.N end or C end extend with insertion all should not be considered as reducing concordance.Know method and computer program for comparison.Concordance percentage ratio can pass through the standard alignment algorithm, for example people such as Altshul ((1990) J.Mol.Biol., basic local comparison research tool (the Basic Local Alignment Search Tool that 215:403410) describes; BLAST); People such as Needleman ((1970) J.Mol.Biol., algorithm 48:444453); Or people such as Meyers ((1988) Comput.Appl.Biosci., algorithm 4:1117) is measured.One group of parameter can be that the gap point penalty is 12, to extend point penalty be 4 and to move frame gap point penalty be 5 Blosum62 rating matrix in the gap.Concordance percentage ratio between two seed amino acids or the nucleotide sequence also can use E.Meyers and W.Miller ((1989) CABIOS, algorithm 4:11-17) is measured, this algorithm has been incorporated in the ALIGN program (2.0 editions), use PAM120 weight residue table (weight residue table), gap length point penalty be 12 and the gap point penalty be 4.

" aminoacid " for example refers to all naturally occurring L-a-amino acids and comprises D-aminoacid.Single-letter or the trigram title identification of aminoacid by knowing.

Term " aminoacid sequence variant " refers to as comparing the molecule that aminoacid sequence has some differences with sequence of the present invention.The amino acid sequence of polypeptide variant of the present invention that for example has a particular sequence still can be in conjunction with human IL-17 or the IL-6 that for example suppresses the human dermal fibroblast that IL-17 induces produce.Alternative variations is the variant that removes at least one amino acid residue and insert different aminoacids at same position in for example having the polypeptide of the present invention of particular sequence.These substitute and can be single substituting, and wherein only aminoacid is through substituting in the molecule, or it can be and substitute more, wherein with two or more aminoacid in a part through substituting.Insert variant in for example having the polypeptide of the present invention of particular sequence, inserting one or more amino acid whose variant at the aminoacid place of next-door neighbour's ad-hoc location.Next-door neighbour's aminoacid means with amino acid whose α-carboxyl or alpha-amido functional group and is connected.The disappearance variant is for removing one or more amino acid whose variant in for example having the polypeptide of the present invention of particular sequence.The disappearance variant is one or two aminoacid of disappearance in the specific region of molecule generally.

As used herein, " treatment effective dose " refers to IL-17 antagonist (IL-17 binding molecule (IL-17 antibody for example for example, Su Jin monoclonal antibody for example) or IL-17 receptors bind molecule (for example IL-17 receptor antibody)) when single dose or multiple dose are applied to individuality (such as human patients), effectively treat, prevent, cure, postpone disease or disease recurrence, reduce its severity, improve its at least one symptom, or prolong individual survival period and exceed the amount of survival period of expecting when not having this treatment and existing.When the single active component that is applied to use separately (for example IL-17 antagonist, for example IL-17 binding molecule (for example IL-17 antibody or its Fab)), this term refers to separate constituent.When being applied to make up, this term refers to produce the combined amount of the active component (no matter still being the while combined administration continuously) of therapeutical effect.

Term " treatment " refers to control property or prophylactic treatment and healing property or amelioration of disease treatment, comprise treatment be in the risk that catches or suspect the patient that caught and ill in or be diagnosed as the patient who suffers from disease or medical science condition of illness, and comprise the inhibition clinical recurrence.Can treat the individuality that has the individual of medical conditions or finally may obtain this disease, with prevention, cure disease or recurrence disease, postpone its outbreak, reduce its severity or improve its one or more symptom, or prolong individual survival period and exceed desired survival period when not having this treatment and existing.

Term used herein " inflammatory arthritis " refers to relate to the various joints patient's condition of immune system and inflammation, and comprises autoimmune disease, for example rheumatoid arthritis.Limiting examples comprises seronegativity spinal joint pathological changes (for example AS), conjunctivo-urethro-synovial syndrome (Reiter ' s syndrome), PsA, enteropathic arthritis and other arthrosiss (for example RA), juvenile rheumatoid arthritis and generalized seizures rheumatoid arthritis, crystalline arthritis (gout, pseudogout, the hydroxyapatite gout), polymyalgia rheumatica, amyloid arthritis, pigmented villonodular synovitis, synovial chondromatosis, hemophilic arthritis and reactive synovitis.In some embodiments of disclosed method, scheme, purposes, test kit and pharmaceutical composition, the patient suffers from inflammatory arthritis.

Term used herein " ankylosing spondylitis ", " AS " reach " spinal joint pathological changes " and refer to be characterised in that the chronically inflamed inflammatory arthritis in joint, and it can comprise recommends ilium (sacroilium) in spinal column and the pelvis, and it can cause spinal column finally to merge.That can use AS suffers from AS through revising New York standard or ASAS mesinae SPA standard (2009) diagnosis patient.In some embodiments of disclosed method, scheme, purposes, test kit and pharmaceutical composition, the patient suffers from AS.

Term used herein " arthritic psoriasis " reaches " PsA " and refers to the often inflammatory arthritis relevant with the skin psoriasis.Can use such as Moll and Wright standard, through revising ESSG standard, McGonagle standard, arthritic psoriasis criteria for classification (Classification Criteria for Psoriatic Arthritis) (CASPAR) multiple standards diagnosis patient such as standard suffer from PsA.In some embodiments of disclosed method, scheme, purposes, test kit and pharmaceutical composition, the patient suffers from PsA.

" rheumatoid arthritis " used herein or " RA " refer to influence many tissues and organ but mainly attack chronic, the general inflammatory arthritis of synovial joints.The 2010ACR/EULAR standard can be used for diagnosing the patient to suffer from RA.In some embodiments of disclosed method, scheme, purposes, test kit and pharmaceutical composition, the patient suffers from RA.

Term used herein " 2010ACR/EULAR standard " refers to the 2010 Americanism damp disease association/European rheumatism alliance standard at RA, referring to people such as Aletaha (2010) Ann.Rheum.Dis.69:1580-1588.This standard suffers from rheumatoid arthritis for the patient is categorized as, described in table 1.

" C-reactive protein " used herein reaches " CRP " and refers to change of serum C-reactive protein, namely is generally used for indicating the plasma protein that the acute stage of inflammation replys.CRP level in the blood plasma can arbitrary concentration provide, for example, and mg/dl, nmol/L.Can measure the CRP level by multiple well-known process, described method for example radioimmunodiffusion, electroimmunoassay, immunoturbidimetry, ELISA, nephelometry, fluorescenee polarization immunoassay and laser is surveyed muddy method.The test of CRP can be adopted standard C RP test or high sensitivity CRP (hs-CRP) test (namely can use laser to survey the high sensitivity testing of the low CRP level in the muddy method measuring samples).Can be available from different company for detection of the test kit of CRP level, for example Calbiotech company, Cayman Chemical, Roche Diagnostics company, Abazyme, DADE Behring, Abnova company, Aniara company, Bio-Quant company, Siemens Healthcare Diagnostics etc.

" high CRP level " used herein refer to such as in the 2010ACR/EULAR standard definition be higher than normal CRP level (people (2010) Ann.Rheum.Dis.69:1580-88 such as Aletaha).According to the 2010ACR/EULAR standard, normal/abnormal CRP is based on local laboratory standard.Each local laboratory is adopted the cutoff of (height) CRP unusually based on the rule that this laboratory calculates normal maximum CRP.The doctor arranges local laboratory to carry out the CRP test usually, and the rule that local laboratory uses this laboratory to be used for the normal CRP of calculating is reported normal or unusual (low or high) CRP.Therefore, unless context indicate in addition, otherwise " high CRP level " used herein not desire represent special value, this be because each laboratory and analyze between think that normal CRP value can be different.In some embodiments of the application, " high CRP level " is〉about 10mg/L (for example 10mg/L), about 20mg/L (for example 20mg/L) or about 30mg/L (for example 30mg/L).Assessed when baseline, be called " the baseline CRP " of CRP level.The high CRP level of baseline can be called " the baseline CRP of rising " or " high baseline CRP ".In some embodiments of disclosed method, scheme, purposes, test kit and pharmaceutical composition, the patient has high baseline CRP (or hsCRP) or high CRP level (or hsCRP).Term " hsCRP " refers to as passing through the CRP level in the blood of high sensitivity CRP thermometrically.

" erythrosedimentation speed " used herein, " ESR ", " rate of settling " (" sedimentation rate " reaches " sedrate ") refer to the erythrocytic rate of settling in patient's sample (for example, plasma sample).The existence of ESR reflection plasma viscosity and acute phase protein, and usually with " mm/hr " report.Determine ESR by the distance that the measurement erythrocyte precipitates in time in pipe.Typical case ESR method of testing is utilized Westergren test, the Zero Energy Thermonuclear Assembly (Zeta) rate of settling (ZSR) test and Wintrobe test.(referring to Moseley and Bull (1982) Clin.Lab Haematol.4:169-78; People such as Miller, (1983) Br Med J (Clin Res Ed) 286 (6361): people (1996) J.Intern.Med.240 (3): 125-310 such as 266, Wetteland P, it is all incorporated herein by reference in full).The commercial reagent box that is used for measurement ESR can be available from (for example) ARKRAY USA, BD Diagnostic Systems and Polymedco company.The ESR instrument can be referring to (for example) United States Patent (USP) 6974701, and from different company, for example Steellex Scientific, Nicesound electronics, inc., Globe Scientific company, Alifax, AnalysisInstrument AB, Streck Laboratories, PolyMed company and Quantimetrix.

" high ESR " used herein refer to such as in the 2010ACR/EULAR standard definition be higher than normal ESR (people (2010) Ann.Rheum.Dis.69:1580-88 such as Aletaha).According to the 2010ACR/EULAR standard, normal/abnormal ESR is based on local laboratory standard.Each local laboratory is adopted the cutoff of (height) ESR unusually based on the rule that this laboratory calculates normal maximum ESR.The doctor arranges local laboratory to carry out the ESR test usually, and local laboratory uses laboratory to be used for calculating the normal or high ESR of rule report of normal ESR.Therefore, unless context indicate in addition, otherwise " high ESR " used herein not desire represent special value, this be because each laboratory and analyze between be considered as normal ESR value can be different.In some embodiments of disclosed method, scheme, purposes, test kit and pharmaceutical composition, the patient has high ESR.

" rheumatoid factor " used herein or " RF " refer to that it often is stored among the RA patient at the autoantibody of the Fc part of IgG antibody." RF " used herein comprises arbitrary RF isotype, for example IgG, IgE, IgM and IgA.Can use the multiple technical Analysis RF that knows, described technology can be used for determining the existence of specific antibodies or not existing that for example, muddy method test etc. is tested, surveyed in elisa assay, coagulation.Can be in many ways by laboratory report RF content, for example IU/ml, unit/ml and titre (use the dilution test can dilute how many patient's blood samples to measure before no longer detecting RF, for example, titre 1:80 represents more can detect RF than titre 1:20).The RF test kit can be available from (for example) IBL-America (Immuno-Biological Laboratories).

For the seropositive patient of RF is called " RF+ " in this article.Similarly, if patient's sample has RF, then this sample is " RF+ ".The rule that each local laboratory calculates normal maximum RF based on this laboratory is adopted the cutoff of normal RF level.As being advised by people such as Aletaha (2010) Ann.Rheum.Dis.69:1580-1588, based on the upper limit [ULN] of the normal value of corresponding laboratory tests and analysis the patient is considered as RF+; If measured value is greater than the ULN of corresponding laboratory tests and analysis, then the patient is RF+.Therefore, unless context indicate in addition, otherwise " RF+ " used herein not desire represent special value because each laboratory and analyze between ULN can be different.As limiting examples, when test, be 14-60 unit/mL the normal range of RF in the blood that laboratory X provides.When test, be≤40IU/ml the normal range of RF in the blood that laboratory Y provides.When test, be the titre of 1:20 to 1:80 the normal range of RF in the blood that laboratory Z provides.Therefore, if laboratory X returns the RF level greater than 60 units/mL, if laboratory Y returns the RF value greater than 40IU/ml, or if laboratory Z returns the RF titre greater than 1:80, then the patient can be RF+.In some embodiments of disclosed method, scheme, purposes, test kit and pharmaceutical composition, the patient is RF+.

Term " seropositivity " is used for meaning the patients serum having predetermined substance (for example RF).

" anti-citrulline protein antibodies " used herein, " ACPA ", " anti-cyclic citrulline peptide antibody " reach the autoantibody that " anti-CCP " refers to the citrulline amino acid residue on the conjugated protein, and it can be found in RA patient's joint.The cyclic citrulline peptide is used for testing in vitro (for example elisa assay) to determine existing of ACPA in the blood samples of patients; Therefore, ACPA is also referred to as " anti-CCP " antibody.Can use the multiple technical Analysis ACPA level of knowing, described technology can be used for the existence of definite specific antibodies or does not exist, for example, and coagulation, elisa assay etc.ACPA has commercially available, for example,

Anti-CCP test from Axis-Shield Diagnostics company limited (UK) and

Test kit is from Abbot Diagnonstics (Germany).

For the seropositive patient of ACPA is called " ACPA+ " in this article.Similarly, if patient's sample has ACPA, then this sample is " ACPA+ ".The rule that each local laboratory calculates normal maximum ACPA based on this laboratory is adopted the cutoff of normal ACPA content.As being advised by people such as Aletaha (2010) Ann.Rheum.Dis.69:1580-1588, based on the upper limit of normal [ULN] of laboratory tests out of the ordinary and analysis, the patient is regarded as ACPA+; If record the value greater than [ULN] of these laboratory tests and analysis, then the patient is ACPA+.Therefore, unless context indicate in addition, otherwise " ACPA+ " used herein not desire represent special value because each laboratory and analyze between ULN can be different.As limiting examples, when test, lab A provides the term of reference of the ACPA in the blood, for＜20EU (ELISA unit arbitrarily).When test, laboratory B provides the term of reference of the ACPA in the blood, for＜5U/ml.Therefore, if lab A is returned the ACPA value greater than 20EU, or if laboratory B returns the ACPA value greater than 5U/ml, then the patient can be ACPA+.In some embodiments of disclosed method, scheme, purposes, test kit and pharmaceutical composition, the patient is ACPA+.

Normal/abnormal and the term of reference of selection ACPA, ESR, RF and CRP can be referring to (for example) Fischbach and Dunning (2009) " A Manual of Laboratory and Diagnositc Tests " (the 8th edition) Wolters Kluwer/Lippincott Williams and Williams, and it is incorporated herein by reference in full.

Term used herein " excessive risk RA patient " is used for the following patient of definition: a) be RF+, ACPA+ or RF+ and ACPA+ the two; And b) have high CRP level (or hsCRP), high ESR or high CRP level and high ESR the two.In some embodiments of disclosed method, scheme, purposes, test kit and pharmaceutical composition, the patient is excessive risk RA patient.In some embodiments, the patient presents at least 1,2,3,4,5,6,7,8,9 or 10 little joint involvement.In some embodiments, the patient presents at least 1,2,3,4,5,6,7,8,9 or 10 big joint involvement.In some embodiments, the patient presents greater than 10 joint involvement, and at least one in the wherein said joint is little joint.In some embodiments, patient's symptom continued at least six weeks.

Any swelling that " joint involvement " found when referring to have a medical check-up or tenderness joint, it can confirm by the imaging evidence of synovitis.According to the position in the joint of getting involved and quantity the classification that the joint distributes is classified, put under in the highest possible classification based on the pattern of joint involvement." big joint " refers to shoulder, elbow, hip, knee joint and ankle." little joint " refers to metacarpophalangeal joints, proximal interphalangeal joint, second to the 5th metatarsophalangeal joints, thumb interphalangeal joint and carpal joint.In some embodiments of disclosed method, scheme, purposes, test kit and compositions, have in 28 joints of patient 〉=have in 6 tenderness joints and 28 joints 〉=6 swollen joint and hsCRP 10mg/L.

" duration of symptoms " when referring to assess, whether the persistent period of the clinical articular synovitis S or S of getting involved (for example pain, swelling, tenderness) of patient oneself report is no matter be therapeutic state.

" select excessive risk RA patient treat " used herein reach " be patient that excessive risk RA patient selection be used for the treatment of based on the patient " reach " selection is used for the treatment of " be used in reference to from bigger group or RA patient based on satisfy excessive risk RA standard (be the patient be RF+, ACPA+ or RF+ and ACPA+ the two; And the patient have high CRP level, high ESR or high CRP level and high ESR the two) the specific RA patient that selects.

Term used herein " had before been treated RA " and had been used in reference to the patient and before used the moist medicine of wind resistance to stand the RA treatment, and for example, the patient is to previous RA therapy, the moist medicine of wind resistance or therapeutic scheme failure, for not enough respondent or do not tolerate.Described patient comprises the patient that those had before been treated through MTX, DMARD and/or biological preparation (for example TNF alpha-2 antagonists) etc.In some embodiments of disclosed method, scheme, purposes, test kit and pharmaceutical composition, the patient had before treated RA.

Term used herein " had not before been treated RA " and had been used in reference to the patient and before do not used the moist medicine of wind resistance to stand the RA treatment, and namely the patient is " just controlling (naive) " patient.In some embodiments of disclosed method, scheme, purposes, test kit and pharmaceutical composition, the patient had not before treated RA.

Used herein previous RA therapy " failure " is referred to: (1) patient does not have significant clinical benefit (the original shortage of effect); (2) patient has and can measure and significant replying, can be better but reply, and for example, be unrealized low RA disease liveness or RA are alleviated (being also referred to as " replying deficiency "); (3) patient well replys back deterioration (the follow-up forfeiture of effect) at first; And (4) patient has and well replys but owing to side effect stops (being also referred to as " not tolerating ").Show TNF reply deficiency (TNF-IR) or not the patient of tolerant T NF can be regarded as the TNF failure.Show that the patient that methotrexate is replied deficiency (MTX-IR) or do not tolerate MTX can be regarded as the MTX failure.Show that the patient that DMARD replys deficiency (DMARD-IR) or do not tolerate DMARD can be regarded as the DMARD failure.In some embodiments of disclosed method, scheme, purposes, test kit and pharmaceutical composition, the patient is TNF failure, MTX failure or DMARD failure.

" therapeutic scheme " means the treatment of diseases pattern, for example, and the mode of administration that during the RA treatment, uses.Therapeutic scheme can comprise induction scheme and Concept of Maintenance.The example that is used for the therapeutic scheme of RA treatment provides in table 2, and it all can not treat excessive risk RA patient.

Table 2: the example of the therapeutic scheme of the Biotherapeutics of rheumatoid arthritis (RA)

Term " induction scheme " or " inducing the period " refer to the therapeutic scheme (or part of therapeutic scheme) for the initial treatment of disease.In some embodiments, disclosed method, purposes, test kit, process and scheme (for example, the method for the treatment of inflammatory arthritis (for example RA) (for example excessive risk RA patient)) adopt induction scheme.The overall goal of induction scheme is to provide high levels of drugs for the patient during the initial period of therapeutic scheme.Induction scheme can (partially or even wholly) be used than the doctor at the medicine of the bigger dosage of the dosage that adopts during the Concept of Maintenance, than doctor's drug administration drug administration or the two more continually during Concept of Maintenance.In some embodiments of disclosed method, purposes, test kit, process and scheme, can during induction scheme, send inductive dose with single high dose infusion form (for example about 30mg/kg).Perhaps, can several times (for example, twice or three times) infusion forms (for example, about 10mg/kg) send inductive dose.Perhaps, can several times (for example, 1,2,3,4,5,6 or more times) subcutaneous injection form (for example, about 75mg to 300mg) send inductive dose.During the induction scheme medicine send can via subcutaneous (s.c.) approach (for example about 75mg is to the dosage subcutaneous delivery (for example subcutaneous, the about 300mg of subcutaneous, the about 150mg of about 75mg is subcutaneous) of about 300mg) or via intravenous (i.v.) approach (for example about 1mg/kg extremely the dosage intravenous of about 30mg/kg (for example send, about 1mg/kg, about 3mg/kg, about 10mg/kg, about 30mg/kg)) or arbitrary other route of administration are (for example, intramuscular, i.m.).In some embodiments of disclosed method, compositions, test kit, purposes and scheme, during at least a portion of induction scheme, use by intravenous and send IL-17 antagonist (for example Su Jin monoclonal antibody).In some embodiments, induction scheme comprises and uses about 1mg/kg to about 30mg/kg, about 1mg/kg extremely about 10mg/kg, the preferred IL-17 antagonist of about 10mg/kg dosage (for example Su Jin monoclonal antibody).In other embodiments, weekly, per two weeks, week about or sent inductive dose in every month, preferably week about.In other embodiments, induction scheme adopts 1 to 10 dosage of IL-17 antagonist (for example Su Jin monoclonal antibody), 3 dosage of preferred IL-17 antagonist (for example Su Jin monoclonal antibody).

Also can use PK information (referring to table 10) but not concrete dosage design is sent the induction scheme of IL-17 antagonist (for example, IL-17 binding molecule (for example IL-17 antibody, for example Su Jin monoclonal antibody) or IL-17 receptors bind molecule (for example IL-17 receptor antibody)).For disclosed purposes, scheme and method (for example, the method for the treatment of inflammatory arthritis (for example RA) (for example excessive risk RA patient)), the technical staff can (for example send the IL-17 antagonist during induction scheme, IL-17 binding molecule (IL-17 antibody for example, Su Jin monoclonal antibody for example) or IL-17 receptors bind molecule (for example IL-17 receptor antibody)), so that about 360 μ g/mL to be provided the average C to about 401 μ g/mL _MaxPerhaps, the technical staff can (for example send the IL-17 antagonist during induction scheme, IL-17 binding molecule (for example IL-17 antibody, for example Su Jin monoclonal antibody) or IL-17 receptors bind molecule (for example IL-17 receptor antibody)), the mankind that think average 90kg provide the average C of about 401 μ g/mL _Max, the about at most 30%-40%[+ of patient's differences or-].Perhaps, the technical staff can (for example send the IL-17 antagonist during induction scheme, IL-17 binding molecule (for example IL-17 antibody, for example Su Jin monoclonal antibody) or IL-17 receptors bind molecule (for example IL-17 receptor antibody)) mankind that think average 75kg provide the average C of about 360 μ g/mL _MaxPerhaps, the technical staff can (for example send the IL-17 antagonist during induction scheme, IL-17 binding molecule (IL-17 antibody for example, Su Jin monoclonal antibody for example) or IL-17 receptors bind molecule (for example IL-17 receptor antibody)), think that the mankind of average 75kg provide the valley concentration that surpasses 80 μ g/mL during 10 weeks.In some embodiments, during the induction scheme the 0th, 2 and 4 when week intravenous send the IL-17 antagonist, the mankind that think average 90kg provide the average C of about 401 μ g/mL _Max, the about at most 30%-40%[+ of patient's differences or-].In some embodiments, during the induction scheme the 0th, 2 and 4 when week intravenous send the IL-17 antagonist, the mankind that think average 75kg provide the average C of about 360 μ g/mL _MaxIn other embodiments, during the induction scheme the 0th, 2 and 4 when week intravenous send the IL-17 antagonist, think that the mankind of average 75kg provide the valley concentration that surpasses 80 μ g/mL during 10 weeks.

Term " Concept of Maintenance " or " keeping the period " refer to be used for keeping patient's therapeutic scheme (or part of therapeutic scheme) of (for example keeping the long-time section of patient (several months or year) to alleviate) during disease treatment.In some embodiments, disclosed method, purposes and scheme (for example, the method for the treatment of inflammatory arthritis (for example RA) (for example excessive risk RA patient)) adopt Concept of Maintenance.Concept of Maintenance (for example can adopt continuous therapy, with rule drug administration such as (every month for example weekly,, every year) at interval) or intermittent treatment is (for example, when therapy discontinued, intermittent therapy, recurrence treatment or reaching specific preassigned [for example, pain, disease performance etc.]) time treatment.The IL-17 antagonist (for example during the Concept of Maintenance, IL-17 binding molecule (for example IL-17 antibody or its Fab, Su Jin monoclonal antibody for example) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)) send can (for example (for example about 75mg be subcutaneous to the dosage subcutaneous delivery of about 300mg for about 75mg via subcutaneous route, about 150mg is subcutaneous, about 300mg is subcutaneous)), or via intravenous route (for example about 1mg/kg (for example sends to the dosage intravenous of about 30mg/kg, about 1mg/kg, about 3mg/kg, about 10mg/kg, about 30mg/kg)), or arbitrary other route of administration (for example, intramuscular, i.m.).In some embodiments of disclosed method, purposes and scheme, during Concept of Maintenance, send IL-17 antagonist (for example Su Jin monoclonal antibody) by subcutaneous administration.In some embodiments, Concept of Maintenance comprises and uses about 75mg to about 300mg, about 75mg extremely about 150mg, the preferred IL-17 antagonist (for example Su Jin monoclonal antibody) of about 75mg or about 150mg dosage.In some embodiments, Concept of Maintenance comprises the IL-17 antagonist (for example Su Jin monoclonal antibody) of using doses in every month.

Also can use PK information (referring to table 9) but not concrete dosage design is sent IL-17 antagonist (for example, the Concept of Maintenance of IL-17 binding molecule (for example IL-17 antibody, for example Su Jin monoclonal antibody) or IL-17 receptors bind molecule (for example IL-17 receptor antibody).For disclosed purposes, scheme and method are (for example, the method for the treatment of inflammatory arthritis (for example RA) (for example excessive risk RA patient)), the technical staff can (for example send the IL-17 antagonist during Concept of Maintenance, IL-17 binding molecule (IL-17 antibody for example, Su Jin monoclonal antibody for example) or IL-17 receptors bind molecule (for example IL-17 receptor antibody)), with the mankind for average 75kg (for example 71kg to 79kg) provide about 9.4 μ g/mL to about 31 μ g/mL (for example, about 9.4 μ g/mL, about 17.3 μ g/mL, about 31 μ g/mL) average steady state valley concentration, the about at most 30%[+ of patient's differences or-].Perhaps, the technical staff can (for example send the IL-17 antagonist during Concept of Maintenance, IL-17 binding molecule (IL-17 antibody for example, Su Jin monoclonal antibody for example) or IL-17 receptors bind molecule (for example IL-17 receptor antibody) think that the mankind of average 75kg provide about 8.0 μ g/mL average steady state valley concentration to about 30.0 μ g/mL (for example, about 8.0 μ g/mL, about 17 μ g/mL, about 30 μ g/mL).In some embodiments, during Concept of Maintenance, sent in every month the IL-17 antagonist with the mankind for average 70kg provide about 9.4 μ g/mL to about 31 μ g/mL (for example, about 9.4 μ g/mL, about 17.3 μ g/mL, about 31 μ g/mL) average steady state valley concentration, the about at most 30%[+ of patient's differences or-].In other embodiments, during Concept of Maintenance, sent the IL-17 antagonist in every month and think that the mankind of average 75kg provide about 8.0 μ g/mL average steady state valley concentration to about 30.0 μ g/mL (for example, about 8.0 μ g/mL, about 17 μ g/mL, about 30 μ g/mL).Perhaps, the technical staff can (for example send the IL-17 antagonist during Concept of Maintenance, IL-17 binding molecule (IL-17 antibody for example, Su Jin monoclonal antibody for example) or IL-17 receptors bind molecule (for example IL-17 receptor antibody)), to provide about 314mg * day/L to about 1323mg * day/L (for example, about 314mg * day/L is to about 1256mg * day/L, for example about 331mg * day/L average A UC τ under the stable state of about 1323mg * day/L) extremely.

Usually measured administration time from the same day (being also referred to as " baseline ") of using the Su Jin monoclonal antibody for the first time.Yet different medical personnel use different naming rules, as shown in following table 3.

Week

0/1

1/2

2/3

3/4

4/5

5/6

6/7

7/8

8/9

9/10

10/11

Deng

The 1st day

0/1

7/8

14/15

21/22

28/29

35/36

42/43

49/50

56/57

63/64

70/71

Deng

The naming rule commonly used of table 3 – dosage regimen.The runic item is the naming rule of using among the application.

It should be noted that the 0th week in some naming rules, can be called for the 1st week, in some naming rules, can be called the 1st day on the 0th day simultaneously.Therefore, different physicians can be specified, for example during the 3rd week/the 21st day, during the 3rd week/the 22nd day, during the 4th week/the 21st day, during the 4th week/gave dosage at the 22nd day, but refer to identical drug dosage schedule.For being consistent, first week of administration used herein was called for the 0th week, and first day with administration is called the 1st day simultaneously.Therefore, can be in (for example at about the 1st day) during the 0th week, in (for example at about the 8th day) during the 1st week, at four inductive doses of (for example at about the 15th day) during the 2nd week and the Su Jin monoclonal antibody of using weekly during (for example at about the 22nd day) provides induction scheme during the 3rd week.Can per 2 weeks (namely week about) (for example, during the 0th week, during the 2nd week, during the 4th week etc.) use inductive dose.Can per 3 weeks (for example, during the 0th week, during the 3rd week, during the 6th week etc.) use inductive dose.Reached for 1 week but use inductive dose every day, for example at the 1st day to the 7th day.Yet, it should be noted that this naming rule only for clarity sake and not should be considered as having restricted.

Term administering instrument used herein " in order to represent any utensil that general is used biological preparation that can be used for, include, but is not limited to pre-filled syringe, bottle and syringe, injection pen, automatic injector, intravenous drip device and bag, paster, gel, pump etc.Use these article, the patient can be from drug administration (also namely drug administration) voluntarily, but or doctor's drug administration.

The application's various aspects more specifically are described in the following little chapters and sections.The full content of all patents, patent application, list of references and other publications is all incorporated herein by reference.

Various disclosed pharmaceutical compositions, scheme, process, purposes, method and test kit (for example utilize the IL-17 antagonist, IL-17 binding molecule (for example IL-17 antibody or its Fab, for example Su Jin monoclonal antibody) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)).

In one embodiment, IL-17 antagonist (for example, IL-17 binding molecule (for example IL-17 antibody or its Fab, for example Su Jin monoclonal antibody)) comprises at least one immunoglobulin heavy chain variable domain (V _H), this V _HComprise hypervariable region CDR1, CDR2 and CDR3 in regular turn, this CDR1 has aminoacid sequence SEQ ID NO:1 (N-Y-W-M-N), this CDR2 has aminoacid sequence SEQ ID NO:2 (A-I-N-Q-D-G-S-E-K-Y-Y-V-G-S-V-K-G), and this CDR3 has aminoacid sequence SEQ ID NO:3 (D-Y-Y-D-I-L-T-D-Y-Y-I-H-Y-W-Y-F-D-L).

In one embodiment, IL-17 antagonist (for example IL-17 binding molecule (for example, IL-17 antibody or its Fab, for example Su Jin monoclonal antibody)) comprises at least one immunoglobulin light chain variable domain (V _L), this V _LComprise hypervariable region CDR1', CDR2' and CDR3' in regular turn, this CDR1' has aminoacid sequence SEQ ID NO:4 (R-A-S-Q-S-V-S-S-S-Y-L-A), and this CDR2' has aminoacid sequence SEQ ID NO:5 (G-A-S-S-R-A-T) and this CDR3' has aminoacid sequence SEQ ID NO:6 (Q-Q-Y-G-S-S-P-C-T).

In one embodiment, IL-17 antagonist (for example IL-17 binding molecule (for example, IL-17 antibody or its Fab, for example Su Jin monoclonal antibody)) comprises at least one immunoglobulin heavy chain variable domain (V _H), this V _HComprise hypervariable region CDR1-x, CDR2-x and CDR3-x in regular turn, this CDR1-x has aminoacid sequence SEQ IDNO:11 (G-F-T-F-S-N-Y-W-M-N), this CDR2-x has aminoacid sequence SEQ ID NO:12 (A-I-N-Q-D-G-S-E-K-Y-Y), and this CDR3-x has aminoacid sequence SEQ ID NO:13 (C-V-R-D-Y-Y-D-I-L-T-D-Y-Y-I-H-Y-W-Y-F-D-L-W-G).

In one embodiment, IL-17 antagonist (for example IL-17 binding molecule (for example, IL-17 antibody or its Fab, for example Su Jin monoclonal antibody)) comprises at least one immunoglobulin V _HDomain and at least one immunoglobulin V _LDomain, wherein: a) immunoglobulin V _HDomain comprises: i) hypervariable region CDR1, CDR2 and CDR3, this CDR1 have aminoacid sequence SEQ ID NO:1, and this CDR2 has aminoacid sequence SEQ ID NO:2, and this CDR3 has aminoacid sequence SEQ ID NO:3; Or ii) hypervariable region CDR1-x, CDR2-x and CDR3-x, this CDR1-x has aminoacid sequence SEQ ID NO:11, and this CDR2-x has aminoacid sequence SEQ IDNO:12, and this CDR3-x has aminoacid sequence SEQ ID NO:13; And b) immunoglobulin V _LDomain comprises hypervariable region CDR1', CDR2' and CDR3', and this CDR1' has aminoacid sequence SEQ ID NO:4, and this CDR2' has aminoacid sequence SEQ ID NO:5, and this CDR3' has aminoacid sequence SEQ ID NO:6.

In one embodiment, IL-17 antagonist (for example IL-17 binding molecule (for example, IL-17 antibody or its Fab, for example Su Jin monoclonal antibody)) comprises at least one immunoglobulin V _HDomain and at least one immunoglobulin V _LDomain, wherein: a) this at least one immunoglobulin V _HDomain comprises the sequence among hypervariable region CDR1, CDR2 and the CDR3, and this CDR1 has aminoacid sequence SEQ ID NO:1, and this CDR2 has aminoacid sequence SEQ ID NO:2, and this CDR3 has aminoacid sequence SEQ ID NO:3; And b) this at least one immunoglobulin V _LDomain comprises the sequence among hypervariable region CDR1', CDR2' and the CDR3', and this CDR1' has aminoacid sequence SEQ ID NO:4, and this CDR2' has aminoacid sequence SEQ ID NO:5, and this CDR3' has aminoacid sequence SEQ ID NO:6.

In one embodiment, IL-17 antagonist (for example IL-17 binding molecule (for example, IL-17 antibody or its Fab, for example Su Jin monoclonal antibody)) comprises at least one immunoglobulin V _HDomain and at least one immunoglobulin V _LDomain, wherein: a) this at least one immunoglobulin V _HDomain comprises the sequence among hypervariable region CDR1-x, CDR2-x and the CDR3-x, and this CDR1-x has aminoacid sequence SEQ ID NO:11, and this CDR2-x has aminoacid sequence SEQ ID NO:12, and this CDR3-x has aminoacid sequence SEQ ID NO:13; And b) this at least one immunoglobulin V _LDomain comprises the sequence among hypervariable region CDR1', CDR2' and the CDR3', and this CDR1' has aminoacid sequence SEQ ID NO:4, and this CDR2' has aminoacid sequence SEQ ID NO:5, and this CDR3' has aminoacid sequence SEQ ID NO:6.

In one embodiment, (for example the IL-17 binding molecule (for example for the IL-17 antagonist, IL-17 antibody or its Fab, for example Su Jin monoclonal antibody)) comprise: the immunoglobulin heavy chain variable domain (V that a) comprises the aminoacid sequence shown in the SEQ ID NO:8 _H); B) comprise the immunoglobulin light chain variable domain (V of the aminoacid sequence shown in the SEQ ID NO:10 _L); C) comprise the immunoglobulin V of the aminoacid sequence shown in the SEQ ID NO:8 _HDomain and comprise the immunoglobulin V of the aminoacid sequence shown in the SEQ ID NO:10 _LDomain; D) comprise the immunoglobulin V of the hypervariable region shown in SEQ ID NO:1, SEQID NO:2 and the SEQ ID NO:3 _HDomain; E) comprise the immunoglobulin V of the hypervariable region shown in SEQ ID NO:4, SEQ ID NO:5 and the SEQ ID NO:6 _LDomain; F) comprise the immunoglobulin V of the hypervariable region shown in SEQ IDNO:11, SEQ ID NO:12 and the SEQ ID NO:13 _HDomain; G) comprise the immunoglobulin V of the hypervariable region shown in SEQ ID NO:1, SEQ ID NO:2 and the SEQ ID NO:3 _HDomain and comprise SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 shown in the immunoglobulin V of hypervariable region _LDomain; Or h) comprises the immunoglobulin V of the hypervariable region shown in SEQ ID NO:11, SEQ ID NO:12 and the SEQ ID NO:13 _HDomain and comprise SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 shown in the immunoglobulin V of hypervariable region _LDomain.

For ease of reference, based on the Kabat definition and as measured and use Chothia and partner's method by X-ray analysis, in following table 4, provide the aminoacid sequence of the hypervariable region of Su Jin monoclonal antibody monoclonal antibody.

Table 4: the aminoacid sequence of the hypervariable region of Su Jin monoclonal antibody.The aminoacid that runic is emphasized is the CDR loop section, and the aminoacid that normal font shows is antibody framework district part.

In preferred embodiments, the two variable domains of heavy chain and light chain has the people source, for example as the SEQ IDNO:10 (variable domains of=light chain, be the amino acid/11 to 109 of SEQ ID NO:10) and SEQ ID NO:8 (variable domains of=heavy chain, the i.e. amino acid/11 to 127 of SEQ ID NO:8) shown in the variable domains of Su Jin monoclonal antibody.The constant region domain preferably also comprises suitable human constant region domain, for example, as " Sequences of Proteins of Immunological Interest ", people such as Kabat E.A., US Department of Health and Human Services, Public Health Service is described in the National Institute of Health.

In some embodiments, IL-17 antagonist (for example IL-17 binding molecule (for example, IL-17 antibody or its Fab, for example Su Jin monoclonal antibody)) comprises the light chain variable domain of SEQ ID NO:10.In other embodiments, IL-17 antagonist (for example IL-17 binding molecule (for example, IL-17 antibody or its Fab, for example Su Jin monoclonal antibody)) comprises the weight chain variable domain of SEQ ID NO:8.In other embodiments, IL-17 antagonist (for example IL-17 binding molecule (for example, IL-17 antibody or its Fab, for example Su Jin monoclonal antibody)) comprises the light chain variable domain of SEQ ID NO:10 and the weight chain variable domain of SEQ ID NO:8.In some embodiments, IL-17 antagonist (for example IL-17 binding molecule (for example, IL-17 antibody or its Fab, for example Su Jin monoclonal antibody)) comprises three CDR of SEQ ID NO:10.In other embodiments, IL-17 antagonist (for example IL-17 binding molecule (for example, IL-17 antibody or its Fab, for example Su Jin monoclonal antibody)) comprises three CDR of SEQ ID NO:8.In other embodiments, IL-17 antagonist (for example IL-17 binding molecule (for example, IL-17 antibody or its Fab, for example Su Jin monoclonal antibody)) comprises three CDR of SEQ ID NO:10 and three CDR of SEQ ID NO:8.According to Chothia and the two definition of Kabat, the CDR of SEQ ID NO:8 and SEQ ID NO:10 can be referring to table 4.

In some embodiments, IL-17 antagonist (for example IL-17 binding molecule (for example, IL-17 antibody or its Fab, for example Su Jin monoclonal antibody)) comprises the light chain domain of SEQ ID NO:15.In other embodiments, IL-17 antagonist (for example IL-17 binding molecule (for example, IL-17 antibody or its Fab, for example Su Jin monoclonal antibody)) comprises the heavy chain domain of SEQ ID NO:17.In other embodiments, IL-17 antagonist (for example IL-17 binding molecule (for example, IL-17 antibody or its Fab, for example Su Jin monoclonal antibody)) comprises the light chain domain of SEQ ID NO:15 and the heavy chain domain of SEQ ID NO:17.In some embodiments, IL-17 antagonist (for example IL-17 binding molecule (for example, IL-17 antibody or its Fab, for example Su Jin monoclonal antibody)) comprises three CDR of SEQ ID NO:15.In other embodiments, IL-17 antagonist (for example IL-17 binding molecule (for example, IL-17 antibody or its Fab, for example Su Jin monoclonal antibody)) comprises three CDR of SEQ ID NO:17.In other embodiments, IL-17 antagonist (for example IL-17 binding molecule (for example, IL-17 antibody or its Fab, for example Su Jin monoclonal antibody)) comprises three CDR of SEQ ID NO:15 and three CDR of SEQ ID NO:17.According to Chothia and the two definition of Kabat, the CDR of SEQ ID NO:15 and SEQ ID NO:17 can be referring to table 4.

Hypervariable region can link to each other with the framework region (being preferably human origin) of any kind of.The suitable frame district is described in people such as KabatE.A., and is the same.Preferred heavy chain framework is the human heavy chain framework, for example the framework of Su Jin antibody mab.Its sequence is made up of (for example) FR1 (amino acid/11 to 30 of SEQ ID NO:8), FR2 (aminoacid 36 to 49 of SEQ ID NO:8), FR3 (aminoacid 67 to 98 of SEQ ID NO:8) and FR4 (amino acid/11 17 to 127 of SEQ ID NO:8) district.To take into account by the hypervariable region of the definite Su Jin monoclonal antibody of X-ray analysis, another preferred heavy chain framework is made up of FR1-x (amino acid/11 to 25 of SEQ ID NO:8), FR2-x (aminoacid 36 to 49 of SEQ ID NO:8), FR3-x (aminoacid 61 to 95 of SEQ ID NO:8) and FR4 (amino acid/11 19 to 127 of SEQ ID NO:8) district in regular turn.In a similar manner, the light chain framework is in regular turn by the amino acid/11 to 23 of FR1'(SEQ ID NO:10), the aminoacid 36 to 50 of FR2'(SEQ ID NO:10), the aminoacid 58 to 89 of FR3'(SEQ ID NO:10) and the aminoacid 99 to 109 of FR4'(SEQ ID NO:10) district forms.

In one embodiment, (for example the IL-17 binding molecule (for example for the IL-17 antagonist, IL-17 antibody or its Fab, Su Jin monoclonal antibody for example)) be selected from human anti-IL-17 antibody, this antibody comprises at least: a) heavy chain immunoglobulin or its fragment, it comprises variable domains, and this variable domains comprises hypervariable region CDR1, CDR2 and CDR3 and constant portion or the fragment of human heavy chain in regular turn; This CDR1 has aminoacid sequence SEQ ID NO:1, and this CDR2 has aminoacid sequence SEQ ID NO:2, and this CDR3 has aminoacid sequence SEQ ID NO:3; And b) light chain immunoglobulin or its fragment, it comprises variable domains, this variable domains comprises hypervariable region CDR1', CDR2' and CDR3' and constant portion or the fragment of human light chain in regular turn, this CDR1' has aminoacid sequence SEQ ID NO:4, this CDR2' has aminoacid sequence SEQ ID NO:5, and this CDR3' has aminoacid sequence SEQ ID NO:6.

In one embodiment, (for example the IL-17 binding molecule (for example for the IL-17 antagonist, IL-17 antibody or its Fab, Su Jin monoclonal antibody for example)) be selected from the strand binding molecule, this strand binding molecule comprises antigen binding site, and it comprises: a) first domain, it comprises hypervariable region CDR1, CDR2 and CDR3 in regular turn, this CDR1 has aminoacid sequence SEQ ID NO:1, and this CDR2 has aminoacid sequence SEQ ID NO:2, and this CDR3 has aminoacid sequence SEQ ID NO:3; And b) second domain, it comprises hypervariable region CDR1', CDR2' and CDR3', and this CDR1' has aminoacid sequence SEQ ID NO:4, and this CDR2' has aminoacid sequence SEQ ID NO:5, and this CDR3' has aminoacid sequence SEQ ID NO:6; And c) peptide connexon, it connects N-C-terminal and second domain terminal or the C-end of first domain and the N-end of second domain of first domain.

Perhaps, (for example the IL-17 binding molecule (for example for the IL-17 antagonist, IL-17 antibody or its Fab, for example Su Jin monoclonal antibody)) can comprise at least one antigen binding site, this antigen binding site comprises at least one immunoglobulin heavy chain variable domain (V _H), its sequence comprises: a) hypervariable region CDR1 (SEQ ID NO:1), CDR2 (SEQ IDNO:2) and CDR3 (SEQ ID NO:3); Or b) hypervariable region CDR1 _i, CDR2 _i, CDR3 _i, this hypervariable region CDR1 _iWith hypervariable region CDR1 shown in SEQ ID NO:1 3, preferred 2, more preferably 1 aminoacid difference, this hypervariable region CDR2 are arranged _iWith hypervariable region CDR2 shown in SEQ ID NO:2 3, preferred 2, more preferably 1 aminoacid difference are arranged; And this hypervariable region CDR3 _iWith hypervariable region CDR3 shown in SEQ ID NO:3 3, preferred 2, more preferably 1 aminoacid difference are arranged; And this IL-17 binding molecule can with about 50nM or littler, about 20nM or littler, about 10nM or littler, about 5nM or littler, about 2nM or concentration littler or more preferably from about 1nM or littler this molecule will about 1nM (=30ng/ml) activity of human IL-17 suppresses 50%, this inhibition activity is to produce to measure at the IL-6 that is induced by the hu-IL-17 in the human corium fibroblast.

Similarly, (for example the IL-17 binding molecule (for example for the IL-17 antagonist, IL-17 antibody or its Fab, for example Su Jin monoclonal antibody)) can comprise at least one antigen binding site, this antigen binding site comprises at least one immunoglobulin heavy chain variable domain (V _H), this V _HComprise in regular turn: a) hypervariable region CDR1-x (SEQ ID NO:11), CDR2-x (SEQ ID NO:12) and CDR3-x (SEQ ID NO:13); Or b) hypervariable region CDR1 _i-x, CDR2 _i-x, CDR3 _i-x, this hypervariable region CDR1 _i-x and hypervariable region CDR1-x shown in SEQ ID NO:11 have 3, preferred 2, more preferably 1 aminoacid difference, this hypervariable region CDR2 _i-x and hypervariable region CDR2-x shown in SEQ ID NO:12 have 3, preferred 2, more preferably 1 aminoacid difference; And this hypervariable region CDR3 _i-x and hypervariable region CDR3-x shown in SEQID NO:13 have 3, preferred 2, more preferably 1 aminoacid difference; And this IL-17 binding molecule can with about 50nM or littler, about 20nM or littler, about 10nM or littler, about 5nM or littler, about 2nM or concentration littler or more preferably from about 1nM or littler this molecule with 1nM (=30ng/ml) activity of human IL-17 suppresses 50%, this inhibition activity is to produce to measure at the IL-6 that is induced by the hu-IL-17 in the human corium fibroblast.

Similarly, (for example the IL-17 binding molecule (for example for the IL-17 antagonist, IL-17 antibody or its Fab, for example Su Jin monoclonal antibody)) can comprise at least one antigen binding site, this antigen binding site comprises at least one immunoglobulin light chain variable domain (V _L), this V _LComprise in regular turn: a) hypervariable region CDR'1 (SEQ ID NO:4), CDR'2 (SEQ ID NO:5) and CDR'3 (SEQ ID NO:6); Or b) hypervariable region CDR1' _i, CDR2' _i, CDR3' _i, this hypervariable region CDR'1 _iWith hypervariable region CDR'1 shown in SEQ ID NO:4 3, preferred 2, more preferably 1 aminoacid difference, this hypervariable region CDR'2 are arranged _iWith hypervariable region CDR'2 shown in SEQ ID NO:5 3, preferred 2, more preferably 1 aminoacid difference are arranged; And this hypervariable region CDR'3 _iWith hypervariable region CDR'3 shown in SEQ ID NO:6 3, preferred 2, more preferably 1 aminoacid difference are arranged; And this IL-17 binding molecule can with about 50nM or littler, about 20nM or littler, about 10nM or littler, about 5nM or littler, about 2nM or concentration littler or more preferably from about 1nM or littler this molecule with 1nM (=30ng/ml) activity of human IL-17 suppresses 50%, this inhibition activity is to produce to measure at the IL-6 that is induced by the hu-IL-17 in the human corium fibroblast.

Perhaps, IL-17 antagonist (for example IL-17 binding molecule (for example, IL-17 antibody or its Fab, for example Su Jin monoclonal antibody)) can comprise heavy chain (V _H) and light chain (V _L) variable domains and this IL-17 binding molecule have at least one antigen binding site, this antigen binding site comprises: a) immunoglobulin heavy chain variable domain (V _H), this domain comprises hypervariable region CDR1 (SEQ ID NO:1), CDR2 (SEQ ID NO:2) and CDR3 (SEQ ID NO :) in regular turn; And immunoglobulin light chain variable domain (V _L), this domain comprises hypervariable region CDR1'(SEQ ID NO:4 in regular turn), CDR2'(SEQ ID NO:5) and CDR3'(SEQ ID NO:6); Or b) immunoglobulin heavy chain variable domain (V _H), this domain comprises hypervariable region CDR1 in regular turn _i, CDR2 _iAnd CDR3 _i, this hypervariable region CDR1 _iWith hypervariable region CDR1 shown in SEQ IDNO:1 3, preferred 2, more preferably 1 aminoacid difference, this hypervariable region CDR2 are arranged _iWith hypervariable region CDR2 shown in SEQ ID NO:2 3, preferred 2, more preferably 1 aminoacid difference are arranged; And this hypervariable region CDR3 _iWith hypervariable region CDR3 shown in SEQ ID NO:3 3, preferred 2, more preferably 1 aminoacid difference are arranged; And immunoglobulin light chain variable domain (V _L), this domain comprises hypervariable region CDR1' in regular turn _i, CDR2' _i, CDR3' _i, this hypervariable region CDR'1 _iWith hypervariable region CDR'1 shown in SEQ ID NO:4 3, preferred 2, more preferably 1 aminoacid difference, this hypervariable region CDR'2 are arranged _iWith hypervariable region CDR'2 shown in SEQ ID NO:5 3, preferred 2, more preferably 1 aminoacid difference are arranged; And this hypervariable region CDR'3 _iWith hypervariable region CDR'3 shown in SEQ ID NO:6 3, preferred 2, more preferably 1 aminoacid difference are arranged; And this IL-17 binding molecule can with about 50nM or littler, about 20nM or littler, about 10nM or littler, about 5nM or littler, about 2nM or concentration littler or more preferably from about 1nM or littler this molecule with 1nM (=30ng/ml) activity of human IL-17 suppresses 50%, this inhibition activity is to produce to measure at the IL-6 that is induced by the hu-IL-17 in the human corium fibroblast.

Perhaps, IL-17 antagonist (for example IL-17 binding molecule (for example, IL-17 antibody or its Fab, for example Su Jin monoclonal antibody)) can comprise heavy chain (V _H) and light chain (V _L) variable domains and this IL-17 binding molecule have at least one antigen binding site, this antigen binding site comprises: a) immunoglobulin heavy chain variable domain (V _H), this domain comprises hypervariable region CDR1-x (SEQ ID NO:11), CDR2-x (SEQ ID NO:12) and CDR3-x (SEQ ID NO:13) in regular turn; And immunoglobulin light chain variable domain (V _L), this domain comprises hypervariable region CDR1'(SEQ ID NO:4 in regular turn), CDR2'(SEQ ID NO:5) and CDR3'(SEQ ID NO:6); Or b) immunoglobulin heavy chain variable domain (V _H), this domain comprises hypervariable region CDR1 in regular turn _i-x, CDR2 _i-x and CDR3 _i-x, this hypervariable region CDR1 _i-x, CDR2 _i-x, CDR3 _i-x, this hypervariable region CDR1 _i-x and hypervariable region CDR1-x shown in SEQ ID NO:11 have 3, preferred 2, more preferably 1 aminoacid difference, this hypervariable region CDR2 _i-x and hypervariable region CDR2-x shown in SEQ ID NO:12 have 3, preferred 2, more preferably 1 aminoacid difference; And this hypervariable region CDR3 _i-x and hypervariable region CDR3-x shown in SEQ ID NO:13 have 3, preferred 2, more preferably 1 aminoacid difference; And immunoglobulin light chain variable domain (V _L), this domain comprises hypervariable region CDR1' in regular turn _i, CDR2' _i, CDR3' _i, this hypervariable region CDR'1 _iWith hypervariable region CDR'1 shown in SEQ ID NO:4 3, preferred 2, more preferably 1 aminoacid difference, this hypervariable region CDR'2 are arranged _iWith hypervariable region CDR'2 shown in SEQ ID NO:5 3, preferred 2, more preferably 1 aminoacid difference are arranged; And this hypervariable region CDR'3 _iWith hypervariable region CDR'3 shown in SEQ ID NO:6 3, preferred 2, more preferably 1 aminoacid difference are arranged; And this IL-17 binding molecule can with about 50nM or littler, about 20nM or littler, about 10nM or littler, about 5nM or littler, about 2nM or concentration littler or more preferably from about 1nM or littler this molecule with 1nM (=30ng/ml) activity of human IL-17 suppresses 50%, this inhibition activity is to produce to measure at the IL-6 that is induced by the hu-IL-17 in the human corium fibroblast.

Human IL-17 antibody disclosed herein can comprise with the heavy chain shown in the SEQ ID NO:17 basically consistent heavy chain and with the consistent light chain basically of the light chain shown in the SEQ ID NO:15.Human IL-17 antibody disclosed herein can contain the heavy chain that comprises SEQ ID NO:17 and the light chain that comprises SEQ ID NO:15.

Human IL-17 antibody disclosed herein can comprise: a) heavy chain, and it comprises aminoacid sequence and aminoacid sequence shown in the SEQ ID NO:8 consistent variable domains and the constant portion of human heavy chain basically; And b) light chain, it comprises aminoacid sequence and aminoacid sequence shown in the SEQ ID NO:10 consistent variable domains and the constant portion of human light chain basically.

Can in various tests (comprise described in WO2006/013107 as described in test), test the inhibition to the combination of IL-17 and its receptor easily.Term " to same degree " means in the mentioned a kind of test of this paper, and reference molecule and derived molecules present consistent basically IL-17 at statistical basis and suppress active (referring to the embodiment 1 of WO2006/013107).For example, when testing described in the embodiment 1 of WO2006/013107, IL-17 binding molecule disclosed herein suppresses the IC of human IL-17 (inhibition that the IL-6 that in human corium fibroblast human IL-17 is induced produces) ₅₀Common IC than corresponding reference molecule ₅₀Low about 10nM, more preferably low about 9nM, 8nM, 7nM, 6nM, 5nM, 4nM, 3nM, 2nM or about 1nM are preferably substantially the same.Perhaps, used test can be that solubility IL-17 receptor (for example, the human IL-17R/Fc construct of the embodiment 1 of WO2006/013107) and the application's IL-17 binding molecule is to the competitive inhibition test of IL-17 combination.

The application (for example also comprises the IL-17 antagonist, IL-17 binding molecule (for example IL-17 antibody or its Fab, Su Jin monoclonal antibody for example)), wherein one or more in the amino acid residue of CDR1, CDR2, CDR3, CDR1-x, CDR2-x, CDR3-x, CDR1', CDR2' or CDR3' or framework (only several (for example, 1 to 4) for example change by the sudden change (for example direct mutagenesis) of corresponding DNA sequence usually.The application comprises the DNA sequence of the described IL-17 binding molecule through changing of coding.Particularly, the application comprises the IL-17 binding molecule, and wherein one or more residues of CDR1' or CDR2' change from residue shown in SEQ ID NO:4 (at CDR1') and the SEQ ID NO:5 (at CDR2').

The application also comprise human IL-17 is had a binding specificity the IL-17 antagonist (for example, IL-17 binding molecule (for example IL-17 antibody or its Fab, Su Jin monoclonal antibody for example)), particularly can suppress IL-17 and its receptors bind IL-17 antibody and can be with about 50nM or littler, about 20nM or littler, about 10nM or littler, about 5nM or littler, about 2nM or littler, or more preferably from about 1nM or littler this molecule concentration with 1nM (=30ng/ml) activity of human IL-17 suppresses the IL-17 antibody of 50% (this inhibition activity is to produce to measure at the IL-6 that is induced by the hu-IL-17 in the human corium fibroblast).

The application provides the method for the treatment of RA, described method comprises IL-17 antagonist to the individuality of suffering from RA (for example excessive risk RA patient) administering therapeutic effective dose, and (for example the IL-17 binding molecule (for example, IL-17 antibody or its Fab, for example Su Jin monoclonal antibody)).In some embodiments, in conjunction with the epi-position of mature human IL-17, this epi-position comprises Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 to IL-17 antibody (for example Su Jin monoclonal antibody).In some embodiments, in conjunction with the epi-position of mature human IL-17, this epi-position comprises Tyr43, Tyr44, Arg46, Ala79, Asp80 to IL-17 antibody (for example Su Jin monoclonal antibody).In some embodiments, IL-17 antibody (for example Su Jin monoclonal antibody) is in conjunction with having the epi-position of the IL-17 homodimer of two mature human IL-17 chains, and this epi-position comprises Tyr43, Tyr44, Arg46, Ala79, an Asp80 on Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 and another chain on the chain.The residue numbering plan that is used for the described epi-position of definition is defined as first residue (that is the IL-17A that does not have 23 amino acid N-terminal signal peptide and begin with glycine) with first aminoacid of maturation protein.The sequence description of immaturity IL-17A is in Swiss-Prot clauses and subclauses Q16552.

In some embodiments, the K of IL-17 antibody _DBe about 100pM to 200pM.In some embodiments, IL-17 antibody is used for bioactive IC external and the human IL-17A of 0.67nM ₅₀Be about 0.4nM.In some embodiments, the absolute bioavailability of the IL-17 antibody that subcutaneous (s.c.) uses is about 60% to about 80% scope, and for example about 76%.In some embodiments, the elimination half-life of IL-17 antagonist (for example, IL-17 binding molecule (for example IL-17 antibody, for example Su Jin monoclonal antibody) or IL-17 receptors bind molecule (for example IL-17 receptor antibody)) be about 4 weeks (for example, about 23 to about 30 days, for example about 30 days).In some embodiments, the T of IL-17 antagonist (for example, IL-17 binding molecule (for example IL-17 antibody, for example Su Jin monoclonal antibody) or IL-17 receptors bind molecule (for example IL-17 receptor antibody)) _MaxBe about 7 to 8 days.

In some embodiments of disclosed method, purposes, pharmaceutical composition, test kit, test and therapeutic scheme, the IL-17 antagonist is selected from following: a) IL-17 binding molecule or IL-17 receptors bind molecule; B) Su Jin monoclonal antibody; C) in conjunction with the IL-17 antibody of the epi-position of IL-17, this epi-position comprises Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129; D) in conjunction with the IL-17 antibody of the epi-position of IL-17, this epi-position comprises Tyr43, Tyr44, Arg46, Ala79, Asp80; E) in conjunction with the IL-17 antibody of epi-position of the IL-17 homodimer with two ripe IL-17 protein chains, this epi-position comprises Tyr43, Tyr44, Arg46, Ala79, an Asp80 on Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 and another chain on the chain; F) in conjunction with the IL-17 antibody of epi-position of the IL-17 homodimer with two ripe IL-17 protein chains, this epi-position comprises Tyr43, Tyr44, Arg46, Ala79, the Asp80 on Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 and another chain on the chain, the wherein K of IL-17 binding molecule _DBe about 100pM to 200pM, and wherein the interior half-life of body of IL-17 binding molecule is about 4 weeks; And g) comprises the IL-17 antibody that is selected from following antibody: the immunoglobulin heavy chain variable domain (V that i) comprises the aminoacid sequence shown in the SEQ ID NO:8 _H); Immunoglobulin light chain variable domain (the V that ii) comprises the aminoacid sequence shown in the SEQ ID NO:10 _L); The immunoglobulin V that iii) comprises the aminoacid sequence shown in the SEQ ID NO:8 _HDomain and comprise the immunoglobulin V of the aminoacid sequence shown in the SEQ ID NO:10 _LDomain; The immunoglobulin V that iv) comprises the hypervariable region shown in SEQ ID NO:1, SEQ ID NO:2 and the SEQ IDNO:3 _HDomain; The immunoglobulin V that v) comprises the hypervariable region shown in SEQ ID NO:4, SEQ ID NO:5 and the SEQ ID NO:6 _LDomain; The immunoglobulin V that vi) comprises the hypervariable region shown in SEQ ID NO:11, SEQ IDNO:12 and the SEQ ID NO:13 _HDomain; The immunoglobulin V that vii) comprises the hypervariable region shown in SEQ ID NO:1, SEQ ID NO:2 and the SEQ ID NO:3 _HDomain and comprise SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 shown in the immunoglobulin V of hypervariable region _LDomain; Reach the immunoglobulin V that viii) comprises the hypervariable region shown in SEQ ID NO:11, SEQ ID NO:12 and the SEQ ID NO:13 _HDomain and comprise SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 shown in the immunoglobulin V of hypervariable region _LDomain.

(for example be used for the particularly preferred IL-17 antagonist of disclosed method, purposes, test kit etc., IL-17 binding molecule (for example IL-17 antibody or its Fab, Su Jin monoclonal antibody for example) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)) be human antibodies, the Su Jin monoclonal antibody described in the

embodiment

1 and 2 of WO2006/013107 particularly.Su Jin monoclonal antibody (AIN457) is complete human monoclonal anti-human interleukin-17 A (IL-17A, IL-17) antibody of the reorganization high-affinity of IgG1/ κ isotype.Su Jin monoclonal antibody (for example, referring to WO2006/013107 and WO2007/117749) has high affinity, i.e. K to IL-17 _DFor about 100pM to 200pM and external in and the bioactive IC of about 0.67nM mankind IL-17A ₅₀Be about 0.4nM.Therefore, the Su Jin monoclonal antibody suppresses antigen with the mol ratio of about 1:1.This high binding affinity makes the Su Jin monoclonal antibody be particularly suited for treatment and uses.In addition, the long half-lift of having determined that the Su Jin monoclonal antibody has the utmost point, i.e. about 4 weeks, the time lengthening between this allows to use, this is superior especially character when the chronic lifelong disease for the treatment of (for example rheumatoid arthritis (RA)).

Therapeutic scheme, Therapeutic Method, pharmaceutical composition and purposes

Disclosed IL-17 antagonist (for example, IL-17 binding molecule (for example IL-17 antibody or its Fab, for example Su Jin monoclonal antibody) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)) can be used for treatment, prevent or improve inflammatory arthritis (for example rheumatoid arthritis (RA), spondyloarthropathy, ankylosing spondylitis and arthritic psoriasis).Therefore, described molecule can be used for inducing arthritic sign and symptom variation and structural change, prevent that further joint from corroding, improving articulation structure etc.In some embodiments, the patient who suffers from inflammatory arthritis is RA patient, for example excessive risk RA patient.

The IL-17 antagonist (for example, IL-17 binding molecule (for example IL-17 antibody or its Fab, Su Jin monoclonal antibody for example) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)) can external or stripped use, or be incorporated in the pharmaceutical composition and body in be applied to individuality (for example, human individual) with treatment, improve or prevent (for example) excessive risk RA patient's RA.Pharmaceutical composition can be through the route of administration (for example, Orally administered composition generally include inert diluent or edible carrier) of preparation to be fit to wish.Other limiting examples of route of administration comprise non-through intestinal (for example intravenous), Intradermal, subcutaneous, oral (for example sucking), percutaneous (part), per mucous membrane and rectal administration.The pharmaceutical composition that is fit to each approach of wishing is well-known in the art.

The IL-17 antagonist (for example, IL-17 binding molecule (for example IL-17 antibody or its Fab, for example Su Jin monoclonal antibody) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)) useful as drug compositions with pharmaceutically acceptable carrier combinations the time.Said composition also can contain carrier, various diluent, filler, salt, buffer agent, stabilizing agent, solubilizing agent and other materials well known in the art except IL-17 antagonist (for example Su Jin monoclonal antibody).The characteristic of carrier depends on route of administration.

The pharmaceutical composition that is used for disclosed method also can contain the other treatment agent that is used for the treatment of the specific objective disease.For example, pharmaceutical composition also can comprise antiinflammatory.Described other factors and/or reagent can be included in the pharmaceutical composition to produce cooperative effect with IL-17 antagonist (for example Su Jin monoclonal antibody), or the side effect that the IL-17 binding molecule is caused minimizes.

The application's pharmaceutical composition can be the liposome form, wherein except other pharmaceutically acceptable carriers, the IL-17 antagonist (for example, IL-17 binding molecule (for example IL-17 antibody or its Fab, for example Su Jin monoclonal antibody) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)) also mix with the amphipathic reagent that exists as the micelle in the aqueous solution, insoluble monolayer, liquid crystalization or platy layer with aggregated forms (for example lipid).The lipid that is applicable to Liposomal formulation includes but not limited to monoglyceride, diglyceride, thioester, LYSOLECITHIN SUNLECITHIN A, phospholipid, Saponin, cholic acid etc.

When implementing Therapeutic Method of the present invention, scheme, purposes etc., to the IL-17 antagonist of individual (for example mammal (for example human)) administering therapeutic effective dose (for example, IL-17 binding molecule (for example IL-17 antibody or its Fab, for example Su Jin monoclonal antibody) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)).IL-17 antagonist (for example Su Jin monoclonal antibody) can be used separately or with other therapy combinations (for example, with other therapy combinations that are used for inflammation) according to the application's method.When using altogether with one or more medicine, IL-17 antagonist (for example Su Jin monoclonal antibody) can be used simultaneously or use in regular turn with another medicine.If use in regular turn, then the attending doctor will determine to use the suitable order of IL-17 antagonist (for example Su Jin monoclonal antibody) and other drug.

At the IL-17 of Orally administered treatment effective dose antagonist (for example, IL-17 binding molecule (for example IL-17 antibody or its Fab, Su Jin monoclonal antibody for example) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)) time, bonding agent will be tablet, capsule, powder, solution or elixir form.The application's pharmaceutical composition can contain solid carrier, for example gelatin or adjuvant in addition when using with tablet form.When using with liquid form, can add liquid-carrier, for example the oil in water, oil, animal or plant source (for example Oleum Arachidis hypogaeae semen (wanting prudent about the Semen arachidis hypogaeae anaphylaxis), mineral oil, soybean oil or Oleum sesami) or artificial oil.The pharmaceutical composition of liquid form can further contain for example normal saline solution, dextrose or other sugar juices or such as the each component of glycol such as ethylene glycol, propylene glycol or Polyethylene Glycol.

At the IL-17 antagonist that passes through intravenous, skin or subcutaneous injection administering therapeutic effective dose (for example, IL-17 binding molecule (for example IL-17 antibody or its Fab, Su Jin monoclonal antibody for example) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)) time, it is pyrogen-free non-through the acceptable solution form of intestinal that the IL-17 binding molecule will be.Intravenous, skin or hypodermic pharmaceutical composition also can contain except IL-17 antagonist (for example Su Jin monoclonal antibody) etc. and to ooze carrier, for example sodium chloride, woods Ge Shi (Ringer's) dextrose, dextrose and sodium chloride, lactated Ringer solution or other carriers known in the art.

Pharmaceutical compositions for use can prepare in a usual manner in the disclosed method.In one embodiment, pharmaceutical composition preferably provides with lyophilized form.For using at once, the present composition is dissolved in the suitable aqueous carrier, for example, Injectable sterile water or aseptic buffer saline.If consider the larger volume solution that needs preparation to use by infusion (but not in the mode of injecting), then can preferably when preparation, human serum albumin or patient self heparinized blood be added in the saline.The existence of the physiology inert protein that this is excessive can prevent the antibody loss by the tube for transfusion that is adsorbed to chamber wall and is used for infusion solution.If the use albumin, then suitable concn is 0.5 weight % to the 4.5 weight % that accounts for saline solution.Other preparations comprise liquid or lyophilized formulations.

Certainly, suitably dosage will be looked following and change: for example, the specific IL-17 antagonist that desire is used (for example, IL-17 binding molecule (for example IL-17 antibody or its Fab, for example Su Jin monoclonal antibody) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)), the character of the previous treatment that stood of the character of host, method of application and the patient's condition for the treatment of and the order of severity and patient.At last, the person in charge's medical personnel will determine the amount of the IL-17 antagonist (for example Su Jin monoclonal antibody) that each independent part for the treatment of is used.In some embodiments, the person in charge's medical personnel can use the IL-17 binding molecule of low dosage and observe individuality and reply.In other embodiments, the predose of the IL-17 antagonist of using to individuality (for example Su Jin monoclonal antibody) is higher, and with the downward titration of post dose till the recurrence sign occurring.Can use the heavy dose of of IL-17 antagonist (for example Su Jin monoclonal antibody) and obtain optimum therapeuticing effect until individuality, and can further not increase this dosage this moment usually.

Can be non-through intestinal, intravenous (for example, to elbow or other peripheral veins), mode (is for example used the IL-17 antagonist easily under intramuscular or the percutaneous, IL-17 binding molecule (for example IL-17 antibody or its Fab, for example Su Jin monoclonal antibody) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)).Use persistent period of intravenous (i.v.) therapy of pharmaceutical composition of the present invention will look the situation of the order of severity of the disease for the treatment of and each individual patient and the individual replys and variation to some extent.Also contain subcutaneous (s.c.) therapy of using pharmaceutical composition of the present invention.Medical personnel will determine to use intravenous or the suitable persistent period of endermic method and the time of application of therapy of pharmaceutical composition of the present invention.

Gratifying result (treatment of symptom, prevention, outbreak postpone) show usually dosage for from about 0.05mg to about 30mg per kilogram of body weight, more generally obtain during the extremely about 20mg per kilogram of body weight of about 0.1mg certainly.Administration frequency can be approximately once a day to per approximately 3 months underranges, and for example in per approximately 2 weeks once extremely in the scope once of per approximately 12 weeks, for example per 4 to 8 weeks once.Administration frequency will especially be decided on the stage of therapeutic scheme.

Now be extensive use of antibody as the active ingredient of medicine, comprised product HERCEPTIN ^TM(Qu Sizuo monoclonal antibody (trastuzumab)), RITUXAN ^TM(Rituximab), SYNAGIS ^TM(palivizumab (palivizumab)) etc.The technology of antibody purification to pharmaceutical grade is well-known in the art.Usually antibody (for example antibody of IL-17) is mixed with and prepares non-lyophilized products with the suitable diluents reprovision through aqueous form that intestinal is used or before using.In some embodiments of disclosed method and purposes, IL-17 antagonist (for example, IL-17 antibody, for example Su Jin monoclonal antibody) is formulated as lyophilized products.But suitable lyophilized products preparation reprovision in little liquid volume (for example, 2ml or littler) to allow subcutaneous administration and to can be the antibody aggregation that solution provides low degree.Compositions is aseptic usually when it forms at least.The common apyrogeneity of compositions, for example, each dosage contains＜1EU (endotoxin unit, gauge), and preferred each dosage＜0.1EU.Compositions does not preferably have seitan.In preparation disclosed herein, antibody preferably accounts at least 80 weight % (for example, at least 90 weight %, 95% weight, 97% weight, 98% weight, 99 weight % or more) of the total protein in the preparation.Therefore, antibody is purified form.

Lyophilized products

The freeze drying technology of antibody is well-known in the art, for example, and referring to Rey﹠amp; May (2004) Freeze-Drying/Lyophilization Of Pharmaceutical﹠amp; Biological Products ISBN0824748689, WO92/15331, U.S. patent application case 2008/0286280, WO03/041637, WO2008/116103, WO2008/029908, WO2007/074880, WO03/009817 and WO98/022136, for example, supply is as the antibody product SYNAGIS of lyophilized products ^TM, REMICADE ^TM, RAPTIVA ^TM, SIMULECT ^TM, XOLAIR ^TMAnd HERCEPTIN ^TMWith described antibody reprovision to different ultimate densities, for example, with SIMULECT ^TMReprovision is to the concentration of 4mg/ml antibody, with REMICADE ^TMReprovision is to the concentration of 10mg/ml, HERCEPTIN ^TMTo 21mg/ml, SYNAGIS ^TMAnd RAPTIVA ^TMTo 100mg/ml, and XOLAIR ^TMTo 125mg/ml.

But reprovision the application's lyophilized products is to provide the waterborne compositions that has at least about the anti-IL-17 antibody concentration of 15mg/ml.Antibody concentration can be far above about 15mg/ml, for example〉about 15mg/ml, about 20mg/ml, about 25mg/ml, about 50mg/ml, about 75mg/ml, about 100mg/ml, about 125mg/ml, about 150mg/ml, about 300mg/ml or higher.

Except anti-IL-17 antibody, lyophilized products also can comprise other components, for example is selected from following one or more: (i) sugar; (ii) buffer agent; (iii) surfactant; Reach (iv) stabilizing agent.Described other components (i), each the introducing in (ii) reaching (iii) all are typical, and can make low gathering of anti-IL-17 antibody in the compositions.Component introducing (iv) is favourable, because it has shown the gathering that can further reduce after the storage.

If exist, component (i) is enough to keep before anti-IL-17 antibody is activity and soluble form after storing (under normal operation) and reprovision the lyophilizing under the concentration to (iv) being in.Each component also exists behind reprovision.

Be applicable to that sugar of the present invention includes but not limited to monosaccharide, disaccharide and trisaccharide.For example, sugar can be sucrose, trehalose, Raffinose, maltose, sorbitol or mannitol.Sugar can be sugar alcohol or amino sugar.Sucrose and trehalose (for example, concentration is that about 175mM is to about 300mM, for example about 175mM, about 180mM, about 185mM, about 190mM, about 195mM, about 200mM, about 225mM, about 250mM, about 275mM, about 300mM) are especially available.

Be applicable to that the buffer agent among the present invention includes but not limited to histidine buffer, citrate buffer agent, phosphate buffer, succinate buffer agent, acetate buffer or Tris buffer agent.Histidine buffer (for example, concentration is that about 5mM is to about 50mM, for example about 5mM, about 10mM, about 15mM, about 20mM, about 25mM, about 30mM, about 35mM, about 40mM, about 45mM, about 50mM) is especially available.

Be applicable to that surfactant of the present invention comprises but is not limited to nonionic surfactant, ionic surfactant and amphoteric ionic surfactant.Be used for typical surface activating agent of the present invention and include but not limited to that sorbitan carboxylic esters (for example, sorbitol anhydride list caprylate, the sorbitol anhydride monolaurate, sorbitol anhydride list palm fibre acid esters), the sorbitol anhydride trioleate, fatty acid glyceride (for example, Monooctamoin, monomyristin, glyceryl monostearate), polyglyceryl fatty acid ester (for example, monostearate ten glyceride, distearyl acid ten glyceride, single linoleic acid ten glyceride), polyoxyethylene sorbitan carboxylic ester (for example, Tween-20, polyoxyethylenesorbitan sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitol acid anhydride list palm fibre acid esters, polyoxyethylene sorbitol acid anhydride trioleate, polyoxyethylene sorbitol acid anhydride tristearate), Polyoxyethylene Sorbitol Fatty Acid Esters (for example, the polyoxyethylene sorbitol tetrastearate, Polyoxyethylene sorbitol tetraoleate), the polyoxyethylene fatty acid glyceride (for example, the polyoxyethylene glyceryl monostearate), cithrol (for example, polyglycol distearate), polyoxyethylene alkyl ether (for example, polyoxyethylene lauryl ether), polyoxyethylene polyoxy-propylene (for example, the polyoxyethylene polypropylene glycol, the polyoxyethylene polyoxypropylene propyl ether, the polyoxyethylene polyoxypropylene cetyl ether), polyoxyethylene alkyl phenyl ether (for example, the polyoxyethylene nonylplenyl ether), polyoxyethylene hydrogenated Oleum Ricini (polyoxyethylene castor oil for example, polyoxyethylene hydrogenated Oleum Ricini), polyoxyethylene Cera Flava derivant (for example, the polyoxyethylene sorbitol Cera Flava), the Wool wax alcohols,ethoxylated derivant (for example, Wool wax alcohols,ethoxylated) and polyoxyethylene fatty acid amide (for example, polyoxyethylene 8 stearate amide); The C10-C18 alkyl sulfonic ester (for example, sodium cetanesulfonate, dodecyl sodium sulfate, oleoyl sodium sulfonate), the polyoxyethylene C10-C18 alkyl ether sulfate that is added with average 2 to 4 moles of ethylene oxide unit (for example, the polyoxyethylene sodium lauryl sulfate) and C1-C18 alkyl sulfosuccinate ester salt (for example, lauryl sodium sulfosuccinate); And natural surfactant, for example sucrose ester of lecithin, phosphoglyceride, sphingomyelins (for example, sphingomyelin) and C12-C18 fatty acid.Compositions can comprise one or more in the described surfactant.Preferred surfactant is polyoxyethylene sorbitan carboxylic ester, for example polysorbate20,40,60 or 80.Polysorbate80 (tween (Tween80)) (for example, concentration is about 0.01% to about 0.1%, for example about 0.02%, about 0.04%, about 0.06%, about 0.08%, about 0.1%) is especially available.

Lyophilized products also can comprise active ingredient except antibody.For example, can comprise other drug reagent, for example chemotherapy compound.For example, can comprise methotrexate, and comprise methotrexate sodium in the known lyophilized products.

PH before the lyophilizing of aqueous antibody preparation can be in 4.0 to 8.0 scopes, about 5.5 pH to about 7.4 scopes are typical, for example about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6, about 6.2, about 6.4, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4.

Herein disclosed is the antibody lyophilized products that comprises the anti-IL-17 antibody of about 25mg, 50mg, 75mg, 150mg or 300mg-preferred anti-IL-17 antibody of 75mg to 150mg (for example, 75mg or 150mg).This paper also discloses lyophilized products, and it comprises: IL-17 antibody, for example Su Jin monoclonal antibody; Sugar; Buffer agent; And surfactant.Compositions also can comprise stabilizing agent.

This paper also discloses the method for preparing lyophilized products, and described method comprises following steps: the aqueous solution that (i) prepares the stabilizing agent that comprises IL-17 antibody (for example Su Jin monoclonal antibody), sugar, buffer agent, surfactant and choose wantonly; Reach (ii) this aqueous solution of lyophilizing.

The reprovision thing

Can be before using lyophilized products to the patient, with liquid reprovision agent (for example waterborne liquid) with the lyophilized products reprovision so that fluid composition (hereinafter referred to as " reprovision thing ") to be provided.

Reprovision agent (for example, the agent of aqueous reprovision, for example water) the reprovision lyophilized products of available different volumes (for example, 0.25ml, 0.5ml, 1.0ml, 1.5ml etc.).This step allows that antibody and other components in the lyophilized products dissolves to produce the solution that is suitable for being injected to the patient again.The volume that is used for the water-based material of reprovision determines the concentration of the antibody of gained pharmaceutical composition, and also can determine route of administration.Utilizing volume to carry out reprovision less than the reprovision agent of lyophilizing front volume provides than denseer compositions before the lyophilizing.As indicated above, lyophilized products of the present invention can have waterborne compositions at least about the anti-IL-17 antibody concentration of 75mg/ml (or higher) with generation through reprovision, and can correspondingly select the volume of reprovision agent.

Herein disclosed is the reprovision thing that comprises anti-IL-17 antibody, wherein the antibody concentration of this reprovision thing is at least about 25mg/ml, 50mg/ml, 75mg/ml, 150mg/ml or 300mg/ml, preferred 75mg/ml to 150mg/ml (for example 75mg/ml or 150mg/ml).Ideally, for being conducive to subcutaneous administration IL-17 antagonist, the volume of reprovision thing is less, for example 0.25ml to 2.0ml.

The typical reprovision agent of lyophilized antibodies comprises sterilized water or buffer agent, randomly contains antiseptic.If lyophilized products comprises buffer agent, then this reprovision agent can further comprise buffer agent (it can be identical or different with the buffer agent of lyophilized products) or on the contrary, it can not comprise buffer agent (for example WFI, normal saline).The reprovision thing can comprise pharmaceutical agent, chemotherapy compound for example, and it is conducive to send altogether with antibody.

If exist, above-mentioned component (i) concentration extremely (iv) is enough to keep anti-IL-17 antibody and is being active soluble form behind the reprovision under the normal storage condition, keeps the medicine acceptability simultaneously in use.

Except antibody and water, the reprovision thing also can comprise other components that are derived from lyophilized products and/or reprovision agent.Described component includes but not limited to buffer agent, salt, stabilizing agent, glycol, alcohol, antiseptic, surfactant etc.Comprehensive discussion of described pharmaceutical compositions sees Gennaro (2000) Remington:The Science and Practice of Pharmacy. the 20th edition, among the ISBN:0683306472.

Herein disclosed is the reprovision medicine composition, it comprises: IL-17 antibody, for example Su Jin monoclonal antibody; Sugar; Buffer agent; And surfactant.Compositions also can comprise stabilizing agent.This paper also discloses the method for preparing the reprovision thing, and it comprises freeze-dried mixed thing and the agent of aqueous reprovision, and wherein this lyophilized products comprises IL-17 antibody (for example Su Jin monoclonal antibody), sugar, buffer agent, surfactant and optional stabilizing agent.

Herein disclosed is the method for the treatment of rheumatoid arthritis (RA), it comprises to the IL-17 antagonist of excessive risk RA patient administering therapeutic effective dose.

This paper also discloses the method for the treatment of rheumatoid arthritis (RA), and it comprises: be that excessive risk RA patient selects the patient that treated based on the patient a); And b) to the IL-17 antagonist of this patient's administering therapeutic effective dose.

Herein disclosed is the method for the treatment of rheumatoid arthritis (RA), it comprises to the IL-17 antagonist of patient's administering therapeutic effective dose, and prerequisite is that this patient is based on following standard and is used for the treatment of through selecting: a) for RF+, ACPA+ or be RF+ and ACPA+ simultaneously; And b) have high CRP level, high ESR or high CRP level and high ESR the two.In some embodiments, step of applying comprises: a) use the IL-17 antagonist to the patient during induction scheme; And b) during Concept of Maintenance, uses the IL-17 antagonist to the patient thereafter.

Herein disclosed is the method for the treatment of rheumatoid arthritis (RA), it comprises: a) use the IL-17 antagonist of the dosage of three about 10mg/kg to excessive risk RA patient, each agent of three dosage is sent week about; And b) thereafter after sending for the third time intravenous dosages a beginning in month every month use extremely about 150mg IL-17 antagonist of about 75mg to the patient.

Herein disclosed is the IL-17 antagonist that is used for the treatment of rheumatoid arthritis (RA), it is characterized in that using the IL-17 antagonist to excessive risk RA patient.Herein disclosed is the IL-17 antagonist that is used for the treatment of rheumatoid arthritis (RA), it is characterized in that using the IL-17 antagonist to the patient, it is that excessive risk RA patient is selected and treats that this patient is based on the patient.

Herein disclosed is the IL-17 antagonist that is used for the treatment of excessive risk RA patient.In some embodiments, excessive risk RA patient: be rheumatoid factor seropositivity (RF+), anti-citrulline protein antibodies seropositivity (ACPA+), or be RF+ and ACPA+ simultaneously a); And b) have high C-reactive protein (CRP) content, high erythrosedimentation speed (ESR) or high CRP level and high ESR the two.In some embodiments, high CRP level is 〉=10mg/L, as measured by hsCRP.In some embodiments, high ESR is 〉=28mm/h.

Herein disclosed is the IL-17 antagonist that is used for the treatment of rheumatoid arthritis (RA), it is characterized in that the IL-17 antagonist is: a) use to excessive risk RA patient with three dosage of about 10mg/kg, each agent of three dosage is sent week about; And b) thereafter after sending intravenous dosages for the third time a beginning in month every month with about 75mg extremely the dosage of about 150mg use to the patient.

Herein disclosed is the IL-17 antagonist in the purposes for the preparation of the medicine for the treatment of RA, it is characterized in that using the IL-17 antagonist to excessive risk RA patient.

Herein disclosed is the IL-17 antagonist in the purposes for the preparation of the medicine for the treatment of RA, it is characterized in that using the IL-17 antagonist to excessive risk RA patient during the Concept of Maintenance after induction scheme reaches.

Herein disclosed is the pharmaceutical composition that is used for the treatment of RA, it comprises active ingredient IL-17 antagonist, wherein uses the IL-17 antagonist to excessive risk RA patient during the Concept of Maintenance after induction scheme reaches.

Herein disclosed is the IL-17 binding molecule that is used for the treatment of RA patient or excessive risk RA patient, it is characterized in that the IL-17 binding molecule is: a) use to the patient during induction scheme, this induction scheme provides the average maximal plasma concentration (C of the IL-17 binding molecule of about 360 μ g/ml _Max); And b) use to the patient during Concept of Maintenance thereafter, this Concept of Maintenance provides: i) the average steady state valley concentration of the IL-17 binding molecule between about 8 μ g/ml and about 30 μ g/ml; And/or the ii) average A UC τ of about 331mg * day/L to the stable state of about 1323mg * day/L.

Herein disclosed is and be used for the treatment of psoriasic IL-17 binding molecule, it is characterized in that the IL-17 binding molecule is: a) use to the patient during induction scheme, this induction scheme provides the average maximal plasma concentration (C of the IL-17 binding molecule of about 401 μ g/ml _Max); And b) use to the patient during Concept of Maintenance thereafter, this Concept of Maintenance provides: i) about 9.4 μ g/ml are to the average steady state valley concentration of the IL-17 binding molecule of about 31 μ g/ml; And/or the ii) average A UC τ of about 314mg * day/L to the stable state of about 1256mg * day/L.

Herein disclosed is the IL-17 antagonist for the preparation of the medicine that is used for the treatment of RA, to be this patient be used for the treatment of through selecting based on following standard prerequisite: a) be RF+, ACPA+ or RF+ and ACPA+ the two; B) have high CRP level, high ESR or high CRP level and high ESR the two.

Herein disclosed is the IL-17 antagonist for the preparation of the medicine of the RA that is used for the treatment of the patient, this patient is characterised in that: a) be RF+, ACPA+ or be RF+ and ACPA+ simultaneously; And b) have high CRP level, high ESR or high CRP level and high ESR the two, wherein this medicine through preparation comprising container, the IL-17 antagonist that each container all has a q.s with allow send per unit dosage at least about 75mg to about 150mg IL-17 antagonist.

Herein disclosed is the IL-17 antagonist for the preparation of the medicine of the RA that is used for the treatment of the patient, this patient is characterised in that: a) be RF+, ACPA+ or be RF+ and ACPA+ simultaneously; And b) have high CRP level, high ESR or high CRP level and high ESR the two, wherein to comprise container, each container all has the IL-17 antagonist of q.s and sends per unit dosage at least about 10mg/kg to allow this medicine through preparation.

Herein disclosed is the IL-17 antagonist for the preparation of the medicine of the RA that is used for the treatment of the patient, this patient is characterised in that: a) be RF+, ACPA+ or be RF+ and ACPA+ simultaneously; And b) have high CRP level, high ESR or high CRP level and high ESR the two, wherein allow that with per unit dosage intravenous sends the dosage of about 10mg/kg and prepare this medicine.

Herein disclosed is the IL-17 antagonist for the preparation of the medicine of the RA that is used for the treatment of the patient, this patient is characterised in that: a) be RF+, ACPA+ or be RF+ and ACPA+ simultaneously; And b) have high CRP level, high ESR or high CRP level and high ESR the two, wherein with per unit dosage allow the about 75mg/kg of subcutaneous delivery extremely the dosage of about 150mg IL-17 antagonist prepare this medicine.

Herein disclosed is the patient's who selects to be used for the treatment of RA testing in vitro method: it comprises definite: i, patient whether be RF+, ACPA+ or RF+ and ACPA+ the two; And ii, patient whether have high CRP level, high ESR or high CRP level and high ESR the two.In some embodiments of disclosed testing in vitro method, the patient has improved treatment to following scheme and replys: IL-17 antagonist from the dosage of three doses of about 10mg/kg to this patient that a) use, first dosage is to send during the 0th week, second dosage is to send during the 2nd week, and the 3rd dosage is to send during the 4th week; And a) begin during the 8th week thereafter, every month twice, every month, per two months or every three months are used about 75mg to about 150mg IL-17 antagonist to the patient.

In some embodiments of disclosed method, test kit, purposes, pharmaceutical composition and scheme, excessive risk RA patient: a) be rheumatoid factor seropositivity (RF+), anti-citrulline protein antibodies seropositivity (ACPA+),

Or be RF+ and ACPA+ simultaneously; And b) have high C-reactive protein (CRP) content, high erythrosedimentation speed (ESR) or high CRP level and high ESR the two.In some embodiments, high CRP level is 〉=10mg/L, as measured by hsCRP.In some embodiments, high ESR is 〉=28mm/h.

In some embodiments of disclosed method, test kit, purposes, pharmaceutical composition and scheme, step of applying comprises IL-17 antagonist from the dosage of three doses of about 10mg/kg to this patient's intravenous that use, and each described dosage is all used week about.In some embodiments, step of applying comprises the IL-17 antagonist to the about 75mg of this patient's subcutaneous administration to about 150mg dosage, and each described dosage was all used once in every month.In some embodiments, step of applying comprises: a) use the IL-17 antagonist to excessive risk RA patient during induction scheme; And b) during Concept of Maintenance, uses the IL-17 antagonist to the patient thereafter.

In some embodiments of disclosed method, test kit, purposes, pharmaceutical composition and scheme, induction scheme comprises IL-17 antagonist from the dosage of three doses of about 10mg/kg to the patient that use.In some embodiments, during the 0th week, send first dosage of about 10mg/kg, during the 2nd week, send second dosage of about 10mg/kg, and during the 4th week, send the 3rd dosage of about 10mg/kg.

In some embodiments of disclosed method, test kit, purposes, pharmaceutical composition and scheme, Concept of Maintenance comprises to the patient uses about 75mg to about 300mg IL-17 antagonist.In some embodiments, Concept of Maintenance comprised every month twice, every month, per two months or every three months to the about 75mg of patient's subcutaneous administration to about 300mg IL-17 antagonist.In some embodiments, Concept of Maintenance begins during being included in for the 8th week, and every month twice, every month, per two months or every three months are to the about 75mg of patient's subcutaneous administration to about 150mg IL-17 antagonist.In some embodiments, Concept of Maintenance begins during being included in for the 8th week, and every month to the about 75mg of patient's subcutaneous administration or about 150mgIL-17 antagonist.

In some embodiments of disclosed method, test kit, purposes, pharmaceutical composition and scheme, before using the IL-17 antagonist, the patient has accepted the RA treatment before this, and this treatment comprises uses at least a moist medicine of following wind resistance that is selected from: immunosuppressant, the moist medicine of wind resistance (DMARD) of alleviating disease, pain control medicine, steroid, non-steroidal anti-inflammatory drug (NSAID), cytokine antagonist, bone anabolic agent, anti-bone resorption agent and combination thereof.In some embodiments, before using the IL-17 antagonist, the patient replys deficiency, treatment failure to the treatment that utilizes DMARD, TNF alpha-2 antagonists or methotrexate or does not tolerate.

In some embodiments of disclosed method, test kit, purposes, pharmaceutical composition and scheme, in addition at least a moist medicine of following wind resistance that is selected from of patient's administering therapeutic effective dose: immunosuppressant, DMARD, pain control medicine, steroid, NSAID, cytokine antagonist, bone anabolic agent, anti-bone resorption agent and combination thereof.

In some embodiments of disclosed method, test kit, purposes, pharmaceutical composition and scheme, use the IL-17 antagonist with the dosage form of three doses of about 10mg/kg, each described dosage is all used week about.In some embodiments, use the IL-17 antagonist with about 75mg to the dosage of about 300mg, each described dosage was all used once in every month.

In some embodiments of disclosed method, test kit, purposes, pharmaceutical composition and scheme, the IL-17 antagonist is to use and using to the patient during Concept of Maintenance thereafter to the patient during the induction scheme.In some embodiments, induction scheme comprises IL-17 antagonist three times from the dosage of about 10mg/kg to the patient that use.In some embodiments, during the 0th week, send first dosage of about 10mg/kg, during the 2nd week, send second dosage of about 10mg/kg, and during the 4th week, send the 3rd dosage of about 10mg/kg.

In some embodiments of disclosed method, test kit, purposes, pharmaceutical composition and scheme, excessive risk RA patient: be rheumatoid factor seropositivity (RF+), anti-citrulline protein antibodies seropositivity (ACPA+), or be RF+ and ACPA+ simultaneously a); And b) have high C-reactive protein (CRP) content, high erythrosedimentation speed (ESR) or high CRP level and high ESR the two.

In some embodiments of disclosed method, test kit, purposes, pharmaceutical composition and scheme, induction scheme with the valley concentration of IL-17 binding molecule keep be higher than 80 μ g/ml reach 10 the week periods.In some embodiments, Concept of Maintenance provides about 8 μ g/ml average steady state valley concentration to the IL-17 binding molecule of about 17 μ g/ml.In some embodiments, Concept of Maintenance provides the average steady state valley concentration of the IL-17 binding molecule of about 8 μ g/ml or about 17 μ g/ml.

In some embodiments of disclosed method, test kit, purposes, pharmaceutical composition and scheme, the IL-17 antagonist is IL-17 binding molecule or IL-17 receptors bind molecule.In some embodiments, IL-17 binding molecule or IL-17 receptors bind molecule are to be selected from following IL-17 binding molecule (for example IL-17 antibody): a) Su Jin monoclonal antibody; B) in conjunction with the IL-17 antibody of the epi-position of IL-17, this epi-position comprises Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129; C) in conjunction with the IL-17 antibody of the epi-position of IL-17, this epi-position comprises Tyr43, Tyr44, Arg46, Ala79, Asp80; D) in conjunction with the IL-17 antibody of epi-position of the IL-17 homodimer with two ripe IL-17 protein chains, this epi-position comprises Tyr43, Tyr44, Arg46, Ala79, an Asp80 on Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 and another chain on the chain; E) in conjunction with the IL-17 antibody of epi-position of the IL-17 homodimer with two ripe IL-17 protein chains, this epi-position comprises Tyr43, Tyr44, Arg46, Ala79, the Asp80 on Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 and another chain on the chain, the wherein K of IL-17 binding molecule _DBe about 100pM to 200pM, and wherein the in vivo half-life of IL-17 binding molecule is about 4 weeks; And f) comprises the IL-17 antibody that is selected from following antibody: the immunoglobulin heavy chain variable domain (V that i) comprises the aminoacid sequence shown in the SEQ ID NO:8 _H); Immunoglobulin light chain variable domain (the V that ii) comprises the aminoacid sequence shown in the SEQ ID NO:10 _L); The immunoglobulin V that iii) comprises the aminoacid sequence shown in the SEQ ID NO:8 _HDomain and comprise the immunoglobulin V of the aminoacid sequence shown in the SEQ ID NO:10 _LDomain; The immunoglobulin V that iv) comprises the hypervariable region shown in SEQ ID NO:1, SEQ ID NO:2 and the SEQ IDNO:3 _HDomain; The immunoglobulin V that v) comprises the hypervariable region shown in SEQ ID NO:4, SEQ ID NO:5 and the SEQ ID NO:6 _LDomain; The immunoglobulin V that vi) comprises the hypervariable region shown in SEQ ID NO:11, SEQ IDNO:12 and the SEQ ID NO:13 _HDomain; The immunoglobulin V that vii) comprises the hypervariable region shown in SEQ ID NO:1, SEQ ID NO:2 and the SEQ ID NO:3 _HDomain and comprise SEQ IDNO:4, SEQ ID NO:5 and SEQ ID NO:6 shown in the immunoglobulin V of hypervariable region _LDomain; Reach the immunoglobulin V that viii) comprises the hypervariable region shown in SEQ ID NO:11, SEQ ID NO:12 and the SEQ ID NO:13 _HDomain and comprise SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 shown in the immunoglobulin V of hypervariable region _LDomain.

In the preferred embodiment of disclosed method, test kit, purposes, pharmaceutical composition and scheme, the IL-17 binding molecule is human antibodies.Disclosed method, test kit, purposes, pharmaceutical composition and scheme in addition more preferred in, the IL-17 binding molecule is the Su Jin monoclonal antibody.

Term used herein " has capacity IL-17 antagonist is sent [prescribed dose] to allow container " and (for example is used in reference to given container, bottle, pen, syringe) in be distributed with the IL-17 antagonist part of pharmaceutical composition (for example, as) of the volume that can be used for providing desired amount.For example, if desired amount is 75mg, then the clinicist can from contain the container of IL-17 antibody preparation that concentration is 37.5mg/ml, use 2ml, from contain the container of concentration as the IL-17 antibody preparation of 75mg/ml, use 1ml, from containing concentration as using 0.5ml etc. the container of the IL-17 antibody preparation of 150mg/ml.Under each this situation, the amount that described solution has the IL-17 antagonist all is enough to allow the 75mg dosage of sending expectation.

Term used herein " is formulated as and allows the dosage of sending [prescribed dose] by [route of administration] " that be used in reference to can be via specifying route of administration (for example, subcutaneous or intravenous) uses the IL-17 antagonist (for example IL-17 antibody, for example Su Jin monoclonal antibody) of given pharmaceutical composition so that desired amount to be provided.For example, if the expectation subcutaneous dosage is 75mg, then the clinicist can use 2ml concentration as the IL-17 antibody preparation of 37.5mg/ml, 1ml concentration as the IL-17 antibody preparation of 75mg/ml, 0.5ml concentration as the IL-17 antibody preparation of 150mg/ml etc.Under each situation, the concentration height of described IL-17 antibody preparation is to being enough to allow subcutaneous delivery IL-17 antibody.Subcutaneous delivery need be sent volume less than about 2ml, preferably about 1ml or littler volume usually.

In some embodiments, induction scheme comprises weekly, week about, per three weeks or every around (every month) send and use about 1,2,3,4,5,6 or the intravenous dosages of multi-agent IL-17 antagonist (for example Su Jin monoclonal antibody) (for example Su Jin monoclonal antibody) more, the dosage of preferred potion, two doses or three doses (most preferably three doses) Su Jin monoclonal antibodies.In some embodiments, induction scheme comprises intravenous and uses 10mg/kg IL-17 antagonist (for example Su Jin monoclonal antibody), for example Su Jin monoclonal antibody.

In some embodiments, the form of three intravenous infusions (for example 10mg/kg) week about, namely during the 0th week (for example, the 1st day), during the 2nd week (for example, about the 15th day) and during the 4th week (for example, about the 29th day) use the inductive dose of IL-17 antagonist (for example Su Jin monoclonal antibody).In some embodiments, can per three Wednesdays the form of time intravenous infusion (for example 10mg/kg), i.e. (for example, about the 1st day) during the 0th week, during the 3rd week (for example, about the 22nd day) and during the 6th week (for example, about the 43rd day) use inductive dose.In some embodiments, the form of (every month) three intravenous infusions (for example 10mg/kg) around can be whenever, i.e. (for example, about the 1st day) during the 0th week, during the 4th week (for example, about the 29th day) and during the 8th week (for example, about the 57th day) use inductive dose.

In some embodiments, the form of twice intravenous infusion (for example 10mg/kg) week about, namely during the 0th week (for example, the 1st day) and during the 2nd week (for example, about the 15th day) use the inductive dose of IL-17 antagonist (for example Su Jin monoclonal antibody).In some embodiments, form that can per three all twice intravenous infusions (for example 10mg/kg), i.e. during the 0th week (for example, about the 1st day) and during the 3rd week (for example, about the 22nd day) use inductive dose.In some embodiments, can be whenever around the form of (every month) twice intravenous infusion (for example 10mg/kg), i.e. during the 0th week (for example, about the 1st day) and during the 4th week (for example, about the 29th day) use inductive dose.

In some embodiments, the inductive dose of can single high dose infusion form (for example 30mg/kg) using IL-17 antagonist (for example Su Jin monoclonal antibody).

In other embodiments, induction scheme comprises every day or

subcutaneous administration

1,2,3,4,5,6 or the dosage of more times IL-17 antagonist (for example Su Jin monoclonal antibody) weekly, the weekly dose of preferred three to five times (for example, four times) Su Jin monoclonal antibodies.In some embodiments, but every day or the inductive dose used weekly are that about 75mg of subcutaneous delivery is to about 300mgIL-17 antagonist (for example Su Jin monoclonal antibody) (for example about 75mg extremely about 150mg, for example about 75mg or about 150mg).

In some embodiments, induction scheme comprises subcutaneous dosage every day of using IL-17 antagonist (for example Su Jin monoclonal antibody), for example the Su Jin monoclonal antibody every day subcutaneous dosage (for example, about 75mg is to about 300mg, for example about 75mg is to about 150mg, for example about 75mg or about 150mg), in the time of 1 to 7 day, send.In some embodiments, induction scheme comprises the subcutaneous dosage weekly of using IL-17 antagonist (for example Su Jin monoclonal antibody), and for example the subcutaneous dosage weekly of Su Jin monoclonal antibody was sent during the 0th, 1,2 and 3 weeks.

In other embodiments, the dosage of the Su Jin monoclonal antibody of using to individuality can higher and frequent (namely for first month for the treatment of, weekly), and can being maintained at the patient than low dosage subsequently during induction scheme.

In some embodiments, Concept of Maintenance comprises: if weight in patients is less than 90kg, then to the about 75mg of patient's subcutaneous administration or about 150mg IL-17 binding molecule.In some embodiments, Concept of Maintenance comprises: if weight in patients surpasses or equals 90kg, then to the about 150mg of patient's subcutaneous administration or about 300mg IL-17 binding molecule.

For Concept of Maintenance, can every month twice (be twice of per two week, every month or week about, namely per approximately 14 days), (be per 4 weeks in every month, namely per approximately 28 days), per two months (namely every other month or per 8 weeks, namely per approximately 56 days) or every three months (being per 12 weeks, namely per approximately 84 days) dosage of IL-17 antagonist (for example Su Jin monoclonal antibody) is provided.As used herein, the date of first dosage of Concept of Maintenance is with the last Rapid Dose Calculation of self-induction scheme.Therefore, for example, if the last dosage of induction scheme was provided during the 4th week, then can during the 6th week, (about the 43rd day) send first dosage as the part of every month twice Concept of Maintenance, can during the 8th week, (about the 57th day) send first dosage as the part of every month Concept of Maintenance, can during the 12nd week, (about the 85th day) send first dosage as the part of per two months Concept of Maintenances, can be during the 16th week (about the 113rd day) send first dosage as part of every three months Concept of Maintenance etc.In some embodiments, play beginning the next month (i.e. about 4 weeks) of inducing (for example, subcutaneous or intravenous is induced) dosage and sent Concept of Maintenance first dosage in (every month, per approximately 4 weeks) in every month sending for the last time certainly.In some embodiments, after sending the 3rd dose of intravenous inductive dose, begin to send in every month (every month, per approximately 4 weeks) first dosage of Concept of Maintenance one month (i.e. about 4 weeks).

In some embodiments, Concept of Maintenance comprises uses IL-17 antagonist (for example Su Jin monoclonal antibody), for example about 75mg is to about 300mg (for example about 75mg extremely about 150mg, for example about 75mg or about 150mg), and every month twice, every month, per two months or every three months are sent.In some embodiments, subcutaneous delivery IL-17 antagonist (for example Su Jin monoclonal antibody) during Concept of Maintenance.In a preferred embodiment, sent maintenance dose in every month.In some embodiments, (for example about the 92nd day) sends first maintenance dose during (for example about the 85th day) or the 13rd week during (for example about the 78th day), the 12nd week during (for example about the 71st day), the 11st week during (for example about the 64th day), the 10th week during (for example about the 57th day), the 9th week during (for example about the 50th day), the 8th week during (for example about the 43rd day), the 7th week during the 6th week of therapeutic scheme, and every month subsequently (for example per approximately 4 weeks or per approximately 28 days) sent.In some embodiments, during the 4th, 5,6,7,8,9,10,11 or 12 weeks, preferably during the 8th week, begin, every month twice, every month, per two months or every three months be (for example about 75mg extremely about 150mg, for example about 75mg or about 150mg) IL-17 antagonist (for example Su Jin monoclonal antibody) to the about 75mg of patient's subcutaneous administration to about 300mg.

The preferred therapeutic scheme that is used for the treatment of RA patient (for example excessive risk RA patient) and suffers from the patient of other inflammatory arthritis (for example spondyloarthropathy, ankylosing spondylitis (AS) and arthritic psoriasis (PsA)) is provided in the table 5:

Table 5: treatment RA patient and suffer from the patient's of other inflammatory arthritis (for example spondyloarthropathy, ankylosing spondylitis and arthritic psoriasis) preferred dosage regimen

Should be understood that dosage does not need to provide at the precise time point, for example, can provide in the 24th day to the 34th day (for example) and be predefined in the 29th day dosage.

In some embodiments, disclosed induce and/or Concept of Maintenance in the dosage (depending on the circumstances) of used IL-17 antagonist (for example Su Jin monoclonal antibody) based on weight in patients (for example, whether be lower than according to the patient or surpass the dosage that 75kg, 80kg, 85kg, 90kg, 95kg, 100kg, 105kg etc. determine to be delivered to patient's IL-17 antagonist (for example Su Jin monoclonal antibody)).In one embodiment, if weight in patients is less than or equal to about 80kg, then use about 75mg or about 150mg (for example subcutaneous delivery) to the patient.In one embodiment, if weight in patients is less than or equal to about 90kg, then use about 75mg or about 150mg (for example subcutaneous delivery) to the patient.In one embodiment, if weight in patients is less than or equal to about 100kg, then use about 75mg or about 150mg (for example subcutaneous delivery) to the patient.In another embodiment, if weight in patients surpasses about 80kg, then use about 150mg or about 300mg (for example subcutaneous delivery) to the patient.In another embodiment, if weight in patients surpasses about 90kg, then use about 150mg or about 300mg (for example subcutaneous delivery) to the patient.In another embodiment, if weight in patients surpasses about 100kg, then use about 150mg or about 300mg (for example subcutaneous delivery) to the patient.

Should be understood that for some patient (for example, the treatment of using IL-17 antagonist (for example Su Jin monoclonal antibody) being presented the patient who replys deficiency), may need dosage escalation (for example, during inducing and/or keeping the phase).Therefore, the subcutaneous dosage of IL-17 antagonist (for example Su Jin monoclonal antibody) can be greater than subcutaneous about 75mg to about 300mg, for example about 80mg, about 100mg, about 125mg, about 175mg, about 200mg, about 250mg, about 350mg, about 400mg etc.; Similarly, intravenous dosages can be greater than about 10mg/kg, for example about 11mg/kg, 12mg/kg, 15mg/kg, 20mg/kg, 25mg/kg, 30mg/kg, 35mg/kg etc.Also should be understood that for some patient (for example, the treatment of using IL-17 antagonist (for example Su Jin monoclonal antibody) being presented adverse events or the bad patient who replys), also can require dosage to reduce (for example, during inducing and/or keeping the phase).Therefore, the dosage of IL-17 antagonist (for example Su Jin monoclonal antibody) can be less than subcutaneous about 75mg to about 300mg, for example about 25mg, about 50mg, about 80mg, about 100mg, about 125mg, about 175mg, about 200mg, 250mg etc.; Similarly, intravenous dosages can be less than about 10mg/kg, for example about 9mg/kg, 8mg/kg, 5mg/kg, 4mg/kg, 3mg/kg, 2mg/kg, 1mg/kg etc.

In some embodiments of said method, purposes, pharmaceutical composition, test kit and therapeutic scheme, CRP level 〉=about 3mg/L (for example 3mg/L), 〉=about 5mg/L (for example 5mg/L), 〉=about 10mg/L (for example 10mg/L), 〉=about 15mg/L (for example 15mg/L) is regarded as high CRP level.In some embodiments, CRP level 〉=200nmol/L or 〉=240nmol/L is regarded as high CRP level.In a preferred embodiment, the CRP level is regarded as high CRP level more than or equal to (〉=) about 10mg/L (for example 10mg/L) (as analyzing measured by high sensitivity CRP).In some embodiments, high CRP level is〉about 10mg/L, about 20mg/L or about 30mg/L.

In some embodiments of said method, purposes, pharmaceutical composition, test kit and therapeutic scheme, can determine " high ESR ": normal maximum ESR (mm/h)≤(age (year)+10 (as if women) based on following rule)/2.Therefore, " high ESR "〉(age (year)+10 (if women))/2.In some embodiments, can determine " high ESR ": normal maximum ESR (mm/h)≤(age (year)+5 (as if women) based on following rule)/2.Therefore, " high ESR "〉(age (year+5 (if women))/2.In some embodiments, for the women, ESR 〉=20mm/h is high ESR.In some embodiments, for the male, ESR 〉=15mm/h is high ESR.In a preferred embodiment, ESR is high ESR more than or equal to (〉=) 28mm/h.

In some embodiments of said method, purposes, pharmaceutical composition, test kit and therapeutic scheme, if patient's RF value is greater than 20IU/ml or greater than 30IU/ml, then the patient is RF+.In some embodiments, if patient's RF value greater than 40 units/mL or greater than 60 units/mL (as testing measured by surveying muddy method), then the patient is RF+.In some embodiments, if patient's RF titre greater than 1:20 or greater than 1:80 (as measured by the dilution test), then the patient is RF+.In a preferred embodiment, if patient's RF value is more than or equal to (〉=) 12kU/L (kilounit/liter) (as measured by the muddy method of survey), then the patient is RF+.

In some embodiments of said method, purposes, pharmaceutical composition, test kit and therapeutic scheme, if patient's ACPA value is greater than 1U/ml, greater than 3U/ml or greater than 5U/ml (as testing measured by (for example) anti-CCP ELISA), then the patient is ACPA+.In preferred embodiments, if patient's ACPA value is greater than 20 units/mL (20U), then the patient is ACPA+.

This paper also discloses the method for the treatment of rheumatoid arthritis (RA), it comprises: a) (for example use to excessive risk RA patient, subcutaneous administration) four times or five about 75mg are to about 300mg (about 75mg about 150mg extremely for example, for example about 75mg or about 150mg) dosage the IL-17 antagonist (for example, IL-17 binding molecule (for example IL-17 antibody or its Fab, Su Jin monoclonal antibody for example) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)), all the sending weekly each time of this four times or five times dosage; And b) every month thereafter twice, every month, per two months or every three months are used about 75mg to about 300mg (for example, about 75mg extremely about 150mg, for example about 75mg or about 150mg) IL-17 antagonist (for example Su Jin monoclonal antibody) to the patient.

This paper also discloses the therapeutic scheme that is used for the treatment of RA, and it comprises: the patient who a) suffers from rheumatoid arthritis based on following Standard Selection: i) patient be RF+, ACPA+, RF+ and ACPA+ the two; And ii) patient have high CRP level, high ESR or high CRP level and high ESR the two; And b) (for example uses to the patient weekly, subcutaneous administration) about 75mg is to about 300mg (about 75mg about 150mg extremely for example, for example about 75mg or about 150mg) the IL-17 antagonist is (for example, IL-17 binding molecule (for example IL-17 antibody or its Fab, Su Jin monoclonal antibody for example) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)), around continuing or five weeks; And c) every month thereafter twice, every month, per two months or every three months are used (for example, subcutaneous administration) about 75mg to about 300mg (for example, about 75mg extremely about 150mg, for example about 75mg or about 150mg) IL-17 antagonist to the patient.

Herein disclosed is the method for the treatment of rheumatoid arthritis (RA), it comprises to (for example presenting high baseline CRP level, greater than about 10mg/L, greater than about 20mg/L, greater than about 30mg/L) RA patient's administering therapeutic effective dose the IL-17 antagonist (for example, IL-17 binding molecule (for example IL-17 antibody or its Fab, for example Su Jin monoclonal antibody) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)).

This paper also discloses the therapeutic scheme that is used for the treatment of RA, and it comprises the patient who a) suffers from rheumatoid arthritis based on following Standard Selection: i) patient has high baseline CRP level (for example, greater than about 10mg/L, greater than about 20mg/L, greater than about 30mg/L); And b) (for example about 75mg is to about 150mg to about 300mg i) to use (for example subcutaneous administration) about 75mg to the patient weekly, for example about 75mg or about 150mg) the IL-17 antagonist is (for example, IL-17 binding molecule (for example IL-17 antibody or its Fab, Su Jin monoclonal antibody for example) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)), use four times or five times; Or ii) (for example use (for example intravenous is used) about 10mg/kg IL-17 antagonist to the patient week about, IL-17 binding molecule (for example IL-17 antibody or its Fab, Su Jin monoclonal antibody for example) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)), use three times; And c) every month thereafter twice, every month, per two months or every three months, (for example used to the patient in preferred every month, subcutaneous administration) about 75mg to about 300mg (for example, about 75mg is to about 150mg, for example about 75mg or about 150mg) IL-17 antagonist (for example Su Jin monoclonal antibody).

This paper also provides the method for the treatment of inflammatory arthritis, it comprises induction scheme, for example to the IL-17 antagonist of the inductive dose of suffering from arthritic the patient twice or three times about 10mg/kg that use (for example intravenous is used) (for example, IL-17 binding molecule (for example IL-17 antibody or its Fab, Su Jin monoclonal antibody for example) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)) (preferred three inductive doses), wherein arthritis is selected from rheumatoid arthritis (RA), spondyloarthropathy, ankylosing spondylitis (AS) and arthritic psoriasis (PsA).In some embodiments, first dosage is to send during the 0th week, and second dosage is to send during the 2nd week, and the 3rd dosage is to send during the 4th week.In some embodiments, first dosage is to send during the 0th week, and second dosage is to send during the 3rd week, and the 3rd dosage is to send during the 6th week.In some embodiments, this method further comprises Concept of Maintenance, (for example about 75mg is to about 150mg to about 300mg for example to use (for example subcutaneous administration) about 75mg to the patient, for example about 75mg or about 150mg) IL-17 antagonist (for example Su Jin monoclonal antibody), wherein every month twice, every month, per two months or every three months are used this IL-17 binding molecule to the patient.In some embodiments, the patient is excessive risk RA patient, for example be rheumatoid factor seropositivity (RF+), anti-cyclic citrulline protein antibodies seropositivity (ACPA+), or be RF+ and ACPA+ simultaneously, and have high C-reactive protein (CRP) content, high erythrosedimentation speed (ESR) or high CRP level and high ESR the two.In some embodiments, high CRP level is 〉=10mg/dL.In some embodiments, high ESR is 〉=28mm/h.In other embodiments, inflammatory arthritis is selected from rheumatoid arthritis (RA), spondyloarthropathy, ankylosing spondylitis and arthritic psoriasis.In some embodiments, the patient suffers from RA.In other embodiments, RA patient is excessive risk RA patient.In other embodiments, excessive risk RA patient: be rheumatoid factor seropositivity (RF+), anti-citrulline protein antibodies seropositivity (ACPA+), or be RF+ and ACPA+ simultaneously a); And b) have high C-reactive protein (CRP) level, high erythrosedimentation speed (ESR) or high CRP level and high ESR the two.

In some embodiments, the IL-17 antagonist (for example, IL-17 binding molecule (for example IL-17 antibody or its Fab, Su Jin monoclonal antibody for example) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)) be used for the treatment of with the methotrexate combination and suffer from moderate to the adult patient of serious activity rheumatoid arthritis, described patient replys deficiency to one or more TNF antagonist therapy.In some embodiments, IL-17 antagonist (for example Su Jin monoclonal antibody) is combined in separately or with methotrexate or other moist medicines of wind resistance (DMARD) of alleviating diseases to be suffered from moderate and is used for alleviating sign and symptom (for example, swelling, action limited) to the adult patient of serious activity disease, causes main clinical response, suppresses the progress of structural damage and improve physical function.In some embodiments, IL-17 antagonist (for example Su Jin monoclonal antibody) makes up to be used for alleviating sign and symptom in the patient who suffers from the extremely serious activity rheumatoid arthritis (RA) of moderate, to cause main clinical response, to suppress the progress of structural damage and to improve physical function separately or with methotrexate.In some embodiments, the combination of IL-17 antagonist (for example Su Jin monoclonal antibody) and methotrexate is to be used for alleviating the progress of sign and symptom, inhibition structural damage to the patient of serious activity rheumatoid arthritis and to improve physical function suffering from moderate.In some embodiments, IL-17 antagonist (for example Su Jin monoclonal antibody) is used for the treatment of the adult who suffers from the extremely serious activity rheumatoid arthritis (RA) of moderate.In some embodiments, IL-17 antagonist (for example Su Jin monoclonal antibody) is used for the treatment of adult's moderate to serious activity rheumatoid arthritis (RA) with the methotrexate combination.In some embodiments, IL-17 antagonist (for example Su Jin monoclonal antibody) is alleviated the progress that is used for alleviating sign and symptom and slows down the structural damage of the extremely serious activity rheumatoid arthritis of moderate among the patient who fails in the moist medicine of wind resistance (DMARD) treatment of disease at one or more.In some embodiments, IL-17 antagonist (for example Su Jin monoclonal antibody) uses to be used for alleviating sign and symptom in the adult patient of suffering from the extremely serious activity rheumatoid arthritis of moderate, to cause main clinical response, to suppress the progress of structural damage and to improve physical function simultaneously as monotherapy or with the moist medicine of wind resistance (DMARD) of alleviating disease.In some embodiments, IL-17 antagonist (for example Su Jin monoclonal antibody) is used for the treatment of the adult patient of suffering from the extremely serious activity rheumatoid arthritis of moderate separately or with methotrexate or other DMARD combination, and it replys deficiency to one or more TNF antagonist therapy.

The combination treatment for the treatment of of arthritis

When implementing Therapeutic Method of the present invention or purposes, to the IL-17 antagonist of individual (for example mammal (for example human)) administering therapeutic effective dose (for example, IL-17 binding molecule (for example IL-17 antibody or its Fab, for example Su Jin monoclonal antibody) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)).IL-17 in conjunction with antagonist (for example Su Jin monoclonal antibody) can according to the application's method separately or with the other drug that is used for the treatment of RA and therapy combined administration, for example, with the moist medicine of at least a wind resistance (for example immunosuppressant, the moist medicine of wind resistance (DMARD) of alleviating disease, pain control medicine, steroid, non-steroidal anti-inflammatory drug (NSAID), cytokine antagonist, bone anabolic agent, anti-bone resorption agent and combination thereof) combined administration (for example, dual and triple therapies).IL-17 antagonist (for example Su Jin monoclonal antibody) can be used simultaneously or use in regular turn when using altogether with one or more other drug with another medicine.If use in regular turn, then the attending doctor will determine to use the suitable order of IL-17 antagonist (for example Su Jin monoclonal antibody) and other drug.

The non-steroidal anti-inflammatory drug and the pain controlling agent that are used for the treatment of RA patient (for example excessive risk RA patient) with IL-17 antagonist (for example Su Jin monoclonal antibody) combination comprise propanoic derivatives, acetogenin, the bmap acid derivant, mefenamic acid (fenamic acid) derivant, the Cox inhibitor, for example, Prexige (lumiracoxib), ibuprofen (ibuprophen), fenoprofen (fenoprofen), ketoprofen (ketoprofen), flurbiprofen (flurbiprofen), oxaprozin (oxaprozin), indomethacin (indomethacin), sulindac (sulindac), etodolac (etodolac), ketorolac (ketorolac), nabumetone (nabumetone), aspirin (aspirin), naproxen (naproxen), valdecoxib (valdecoxib), support is examined former times (etoricoxib), MK0966 (rofecoxib (rofecoxib)), acetaminophen (acetominophen), celecoxib (Celecoxib), diclofenac (Diclofenac), tramadol (tramadol), piroxicam (piroxicam), meloxicam (meloxicam), tenoxicam (tenoxicam), Droxicam (droxicam), lornoxicam (lornoxicam), isoxicam (isoxicam), mefenamic acid (mefanamic acid), meclofenamic acid (meclofenamic acid), flufenamic acid (flufenamic acid), tolfenamic acid (tolfenamic), valdecoxib (valdecoxib), parecoxib (parecoxib), etodolac (etodolac), indomethacin, aspirin, ibuprofen, Fei Luokao former times (firocoxib).

The moist medicine of wind resistance (DMARD) that is used for the treatment of RA patient's (for example excessive risk RA patient) alleviation disease with IL-17 antagonist (for example Su Jin monoclonal antibody) combination comprises methotrexate (MTX), anti-malaria medicaments (for example, oxychloroquine (hydroxychloroquine) and chloroquine (chloroquine)), sulfasalazine (sulfasalazine), leflunomide (Leflunomide), azathioprine (azathioprine), ciclosporin (cyclosporin), gold salt (gold salt), minocycline (minocycline), cyclophosphamide (cyclophosphamide), Beracilline (D-penicillamine), minocycline, auranofin (auranofin), tacrolimus (tacrolimus), myocrisin (myocrisin), chlorambucil (chlorambucil).

The biological agent that is used for the treatment of RA patient (for example excessive risk RA patient) with IL-17 antagonist (for example Su Jin monoclonal antibody) combination comprises adalimumab

, Embrel , English monoclonal antibody of sharp former times

TA-650, match trastuzumab

CDP870, the sharp wooden monoclonal antibody of dagger-axe

CNTO148, Antril (Synergen) , Rituximab

, A Baxipu

, holder pearl monoclonal antibody

The other biological medicament that is used for the treatment of RA patient (for example excessive risk RA patient) with IL-17 antagonist (for example Su Jin monoclonal antibody) combination comprise (for example) integrin antagonists (

(natalizumab (natalizumab)), IL-1 antagonist (ACZ885 (Ilaris)), Antril (Synergen) , CD4 antagonist, IL-17 antagonist (LY2439821, RG4934, AMG827, SCH900117, R05310074, MEDI-571, CAT-2200), IL-23 antagonist, IL-20 antagonist, IL-6 antagonist, TNF alpha-2 antagonists (for example, TNF alpha-2 antagonists or TNF α receptor antagonist, for example Pei Naxipu (pegsunercept etc.), BLyS antagonist (for example A Taxipu (Atacicept),

(Baily wood monoclonal antibody (belimumab)), P38 inhibitor, CD20 antagonist (auspicious pearl monoclonal antibody difficult to understand (Ocrelizumab), the appropriate wooden monoclonal antibody (Ofatumumab of method difficult to understand

), interferon gamma antagonist (fragrant auspicious pearl monoclonal antibody (Fontolizumab)).

The steroid (for example glucocorticoid) that is used for the treatment of RA patient (for example excessive risk RA patient) with IL-17 antagonist (for example Su Jin monoclonal antibody) combination comprises prednisolone (Prednisolone), prednisone (Prednisone), dexamethasone (dexamethasone), hydrocortisone (cortisol), cortisone (cortisone), hydrocortisone (hydrocortisone), methylprednisolone (methylprednisolone), betamethasone (betamethasone), triamcinolone (triamcinolone), beclometasone (beclometasome), fludrocortisone (fludrocortisone), deoxycorticosterone (deoxycorticosterone), aldosterone (aldosterone).

The other drug that is used for the treatment of RA patient (for example excessive risk RA patient) with IL-17 antagonist (for example Su Jin monoclonal antibody) combination comprises SB-681323, Rob803, AZD5672, AD452, SMP114, HZT-501, CP-195,543, doxycycline (Doxycycline), vancomycin (vancomycin), CRx-102, AMG108, pioglitazone (pioglitazone), SBI-087, SCIO-469, Cura-100, Oncoxin+Viusid, TwHF, PF-04171327, AZD5672, methoxsalen (Methoxsalen), ARRY-438162, vitamin D-vitamin D2 (ergocalciferol), midalcipran (Milnacipran), paclitaxel (Paclitaxel), GW406381, rosiglitazone (rosiglitazone), SC12267 (4SC-101); LY2439821, BTT-1023, ERB-041, ERB-041, KB003, CF101, ADL5859, MP-435, ILV-094, GSK706769, GW856553, ASK8007, MOR103, HE3286, CP-690,550 (he replaces Buddhist nun (tasocitinib) by rope), REGN88 (SAR153191), TRU-015, BMS-582949, SBI-087, LY2127399, E-551S-551, H-551, GSK3152314A, RWJ-445380, tacrolimus (Tacrolimus)

RAD001, thunder handkerchief ring (rapamune), rapamycin (rapamycin), he replaces Buddhist nun (fostamatinib) good fortune, fentanyl (Fentanyl), XOMA052, CNTO136, JNJ38518168, imatinib (Imatinib), ATN-103, ISIS104838, folic acid, folate, TNF α kinoid, MM-093, the II Collagen Type VI, VX-509, AMG82770, the Marseille is for Buddhist nun (masitinib (AB1010)), LY2127399, ciclosporin (cyclosporine), SB-681323, MK0663, NNC0151-0000-0000, ATN-103, CCX354-C, CAM3001, LX3305, cetrorelix (Cetrorelix), MDX-1342, TMI-005, MK0873, CDP870, tranilast (Tranilast), CF101, mycophenolic acid (and ester), VX-702, GLPG0259, SB-681323, BG9924, ART621, LX3305, T-614, he replaces Buddhist nun's disodium (R935788) good fortune, CCI-779, ARRY-371797, CDP6038, AMG719, BMS-582949, GW856553, rosiglitazone, CH-4051, CE-224,535, GSK1827771, GW274150, BG9924, PLX3397, TAK-783, INCB028050, LY2127399, LY3009104, R788, curcumin (Curcumin (Longvida ^TM)), rosuvastatin (Rosuvastatin), PRO283698, AMG714, MTRX1011A, Malawi's promise (Maraviroc), MEDI-522, MK0663, the STA5326 mesylate, CE-224,535, AMG108, BG00012, ramipril (ramipril), VX-702, CRx-102, LY2189102, SBI-087, SB-681323, CDP870, midalcipran (Milnacipran), PD0360324, PH-797804, AK106-001616, PG-760564, PLA-695, MK0812, ALD518, row ketone (Cobiprostone) before examination, growth hormone (somatropin), tgAAC94 gene therapy carrier, MK0359, GW856553, the Aesop sends azoles (esomeprazole), everolimus (everolimus), the Qu Sizuo monoclonal antibody, bone anabolic agent and anti-bone resorption agent are (for example, PTH, diphosphonate (for example, zoledronic acid (zoledronic acid), JAK1 and JAK2 inhibitor, full JAK inhibitor (Fourth Ring shape pyridone 6 (P6) for example, 325, PF-956980, the sclerosis protein antagonist (for example, be disclosed in WO09047356, WO2000/32773, WO2006102070, US20080227138, US20100028335, US20030229041, WO2005003158, WO2009039175, WO2009079471, WO03106657, WO2006119062, WO08115732, WO2005/014650, WO2005/003158, WO2006/119107, WO2008/061013, WO2008/133722, WO2008/115732, US7592429, US7879322, among the US7744874, its full content [disclosed method all incorporated herein by reference, pharmaceutical composition, used preferred anti-sclerosis protein antibodies and Fab thereof are referring to WO09047356 (being equal to US7879322) in test kit and the purposes, WO06119107 (being equal to US7872106 and US7592429) and WO08115732 (be equal to US7744874] those), ground Shu Dankang (denosumab), the IL-6 antagonist, the CD20 antagonist, the CTLA4 antagonist, the IL-17 antagonist, the IL-8 antagonist, the IL-21 antagonist, the IL-22 antagonist, integrin antagonists ( (natalizumab)), sclerosis protein antagonist, VGEF antagonist, CXCL antagonist, MMP antagonist, sozin antagonist, IL-1 antagonist (comprising the IL-1 beta antagonists) and IL-23 antagonist (for example, receptor bait, antagonist antibody etc.).

In some embodiments, combined administration IL-17 antagonist (for example Su Jin monoclonal antibody) and at least a moist medicine of following wind resistance that is selected from: immunosuppressant, DMARD, pain control medicine, steroid, NSAID, cytokine antagonist, bone anabolic agent, anti-bone resorption agent and combination thereof.In some embodiments, combined administration IL-17 antagonist (for example Su Jin monoclonal antibody) and TNF antagonist, DMARD (for example, MTX, for example dosage weekly of 7.5mg to 30mg), steroid or its combination.

Those skilled in the art should be able to distinguish the suitable dosage of the said medicine of sending altogether with IL-17 antagonist (for example Su Jin monoclonal antibody).

Test kit and goods

Herein disclosed is and (for example can be used for providing the IL-17 antagonist, IL-17 binding molecule (for example IL-17 antibody or its Fab, Su Jin monoclonal antibody for example) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)) test kit (being goods), it is used for the treatment of RA.Described test kit can comprise IL-17 antagonist (for example Su Jin monoclonal antibody) (for example, being liquid or lyophilized form) or comprise the pharmaceutical composition of IL-17 antagonist (for example Su Jin monoclonal antibody).In addition, described test kit can comprise be used to the instrument of using IL-17 antagonist (for example Su Jin monoclonal antibody) (for example, syringe or the pre-pen of filling) and operation instructions.Described test kit can contain the other treatment agent (it is described to see above) that is used for the treatment of RA, and for example, IL-17 antagonist (for example Su Jin monoclonal antibody) combination in itself and the test kit is sent.

Herein disclosed is and comprise following test kit: a) the IL-17 antagonist (for example, IL-17 binding molecule (for example IL-17 antibody or its Fab, for example Su Jin monoclonal antibody) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)); B) use the description of IL-17 antagonist (for example Su Jin monoclonal antibody) to excessive risk RA patient; C) for instrument from IL-17 antagonist (for example Su Jin monoclonal antibody) to the patient that use; And d) randomly, at least a moist medicine of following wind resistance that is selected from for the treatment of effective dose: immunosuppressant, the moist medicine of wind resistance (DMARD) of alleviating disease, pain control medicine, steroid, non-steroidal anti-inflammatory drug (NSAID), cytokine antagonist, bone anabolic agent, anti-bone resorption agent and combination thereof.In some embodiments, excessive risk RA patient: a) be RF+, ACPA+ or RF+ and ACPA+ the two; B) have high CRP level, high ESR or high CRP level and high ESR the two.

Herein disclosed is and comprise following test kit: a) (for example the IL-17 binding molecule (for example for the IL-17 antagonist, IL-17 antibody or its Fab, Su Jin monoclonal antibody for example) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)) or comprise the pharmaceutical composition of IL-17 antagonist, it is used for the treatment of patient's rheumatoid arthritis (RA); And b) describe description from this pharmaceutical composition to the patient that how use, wherein the patient is characterised in that: i) be RF+, ACPA+ or RF+ and ACPA+ the two; And ii) have high CRP level, high ESR or high CRP level and high ESR the two.

This paper also discloses the patient's who selects to carry out the RA treatment testing in vitro method: it comprises definite: i, patient whether be RF+, ACPA+ or RF+ and ACPA+ the two; And ii, patient whether have high CRP level, high ESR or high CRP level and high ESR the two.In some embodiments of institute's method of testing, the expection patient replys the treatment that following scheme has improvement: (for example the IL-17 binding molecule (for example a) i) to use the IL-17 antagonist of dosage of three about 10mg/kg to the patient, IL-17 antibody or its Fab, Su Jin monoclonal antibody for example) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)), first dosage is to send during the 0th week, second dosage is to send during the 2nd week, and the 3rd dosage is to send during the 4th week; Or (for example the IL-17 binding molecule (for example ii) to use the IL-17 antagonist of dosage weekly of about 75mg or about 150mg to the patient, IL-17 antibody or its Fab, for example Su Jin monoclonal antibody) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)) reach four times or five (preferred five times) dosage; And b) begin during the 8th week thereafter, every month twice, every month, per two months or every three months (preferred every month) are used extremely about 300mg IL-17 antagonist of about 75mg to the patient.Can be to the biological sample that extracts from the patient (for example, blood, cartilage, bone, serum etc.) carry out treatment pattern or scheme that described in vitro method and its can be used for determining particular patient, for example, whether use IL-17 antagonist (making up separately or with another chemical compound (for example methotrexate)) or do not select alternative medicine (for example, anti-TNF treatment) to the patient.

But the method for the information of diagnostic method and generation transmission form

Herein disclosed is will be to (for example utilizing the IL-17 antagonist for definite (prediction) RA patient, IL-17 binding molecule (for example IL-17 antibody or its Fab, Su Jin monoclonal antibody for example) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)) the method for probability of favourable the replying for the treatment of (for example, sign and sx, joint damage reduce, quality of life improves etc.).Described method will help the doctor to determine specific RA patient's scheme.

This paper also discloses and has determined that (prediction) RA patient will be to (for example utilizing the IL-17 antagonist, IL-17 binding molecule (for example IL-17 antibody or its Fab, Su Jin monoclonal antibody for example) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)) treatment the method for the probability of replying is arranged, it comprises the following project of analyzing patient's sample: a) rheumatoid factor (RF), anti-citrulline protein antibodies (ACPA) or RF and ACPA; And b) C-reactive protein (CRP), erythrosedimentation speed (ESR) or CRP and ESR the two, wherein if the patient is RF+, ACPA+ or RF+ and ACPA+, and the patient has high CRP level, high ESR or high CRP level and high ESR, and then this patient may reply the RA treatment that utilizes IL-17 antagonist (for example Su Jin monoclonal antibody).In some embodiments, before analytical procedure, at first obtain sample (for example, by extract blood or other biological tissue from the patient) from the patient.

This paper also discloses prediction RA patient will be to (for example utilizing the IL-17 antagonist, IL-17 binding molecule (for example IL-17 antibody or its Fab, Su Jin monoclonal antibody for example) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)) treatment the method for the probability of replying is arranged, whether it comprises determines the patient: a) be RF+ and/or ACPA; And 2) have high CRP level and/or high ESR, wherein if the patient is RF+, ACPA+ or RF+ and ACPA+ and has high CRP level, high ESR or high CRP level and high ESR that then the patient has the probability of replying to increase to the treatment that utilizes the IL-17 antagonist.In some embodiments, before determining step, at first obtain sample (for example, by extract blood or other biological tissue from the patient) from the patient.

This paper also discloses definite RA patient will be to (for example utilizing the IL-17 antagonist, IL-17 binding molecule (for example IL-17 antibody or its Fab, Su Jin monoclonal antibody for example) or IL-17 receptors bind molecule (for example IL-17 antibody or its Fab)) treatment the method for the probability of replying is arranged, it comprises the sample at the baseline content analysis patient of C-reactive protein (CRP), wherein if the patient has the baseline CRP of rising, then the patient may reply the treatment of the RA that utilizes IL-17 antagonist (for example Su Jin monoclonal antibody).In some embodiments, before analytical procedure, at first obtain sample (for example, by extract blood or other biological tissue from the patient) from the patient.

For described diagnosis and method of prognosis, arbitrary usual manner that can be by detecting the factor (RF, ACPA, CRP, ESR) or factor level (for example radioimmunodiffusion, electroimmunoassay, immunoturbidimetry, Western blot, Northern blot, ELISA, nephelometry, fluorescenee polarization immunoassay, laser are surveyed muddy method, coagulation test, survey muddy method test, measure distance (for example, under the ESR situation) that erythrocyte precipitates in time etc. in pipe) is analyzed patient's sample.Term " analysis " reaches the conversion that " determining " contains material, for example, makes this sample be converted into another state from a kind of state by making biological sample (for example blood sample or other tissue samples) stand physical testing.In addition, term used herein " analysis " reaches " determining " and is used in reference to test and/or measurement.Term " at ... analyze patient's sample " and like that being used in reference to can or not exist or the level (directly or indirectly) of specificity factor is tested sample at the existence of the given factor.Should be understood that in the existence of material and represent not existing under the situation of representing different probabilities of a kind of probability and material that then the existence of this material or do not exist can be used for instructing treatment to determine.In some embodiments, before utilizing the IL-17 antagonist for treating, skilled clinicist will determine whether the patient is excessive risk RA patient.

Usually, in case determine the existence of specificity factor or do not exist or the level of specificity factor, then the result can be informed doctor or consultant hereditism or patient or other researcheres.Particularly, can be with this result establishment (cast) but in the information of transmission form, this information can be transmitted or transfer to other researcheres or doctor or consultant hereditism or patient.This form can change and can be tangible or invisible.About the existence of RF and/or ACPA in the test individuality or do not exist and/or the result of the level of CRP and/or ESR can descriptive statement, chart, photo, diagram, image or any other visual form embody.For example, the image of the gel electrophoresis of PCR product can be used for explaining described result.Statement and visual form can be recorded on tangible media (for example paper, computer readable medium (for example floppy disc, compact disk etc.)) or the invisible media (for example, being Email on the Internet or the internal network or the electronic media of network address form).In addition, about the existence of RF and/or ACPA in the test individuality or do not exist and/or the result of the level of CRP and/or ESR also can the form of sound record or via arbitrary suitable medium (for example analog or digital cable run, fiber optic cables etc.) via phone, fax, mobile phone, Internet telephony and transmission like that.All described forms (tangible and invisible) all can constitute " but information of transmission form ".Therefore, can produce Anywhere in the world about the information of test result and data and can transfer to diverse location.For example, when implementing gene type abroad and analyzing, but can above-mentioned transmission form produce and establishment about information and the data of test result.Thus, but can will be test result input U.S. of transmission form.Therefore, but the present invention also contain generation about the existence of the RF in the individuality and/or ACPA or do not exist and/or the method for the information of the transmission form of the level of CRP and/or ESR.

But herein disclosed is the method that the patient who suffers from RA is produced the information of transmission form, it comprises: the following project of a) analyzing patient's sample: i) rheumatoid factor (RF), anti-citrulline protein antibodies (ACPA) or RF and ACPA; And ii) C-reactive protein (CRP), erythrosedimentation speed (ESR) or CRP and ESR the two; And b) but the result of analytical procedure is converted into the information of transmission form.In some embodiments, behind this step of converting, medical personnel (for example doctor) but the information of using transmission form make decision with regard to whether just using IL-17 antagonist disclosed herein to carry out one of therapeutic scheme disclosed herein prescription.In some embodiments, behind this step of converting, but if the information of transmission form differentiates that the patient is excessive risk RA patient, then medical personnel (for example doctor) use the IL-17 antagonist to the patient.

Summary

The full text of all patents that this paper mentions, publication application, publication, list of references and other materials is all incorporated herein by reference.The detailed content of one or more embodiments of the application is described in the above-mentioned explanation of enclosing.Although any similar or be equal to the method for those methods described herein and material and material all can be used in enforcement of the present invention or the test, at present described is preferable methods and material.According to these descriptions and claim, the application's other features, target and advantage are apparent.In description and the claim of enclosing, unless context clearly indicates in addition, otherwise comprising plural number, singulative refers to.Unless otherwise defined, otherwise all technology used herein and scientific terminology all have the meaning of the common same meaning of understanding of those of ordinary skill of the technical field under the application.All patents and the publication quoted in this description are all incorporated into way of reference.Provide following examples more fully to explain the application's preferred embodiment.Described embodiment never is interpreted as limiting the scope of disclosed patent content, and this scope is determined by the claim of enclosing.

Embodiment

Embodiment 1: the purposes (CAIN457F2201) of Su Jin monoclonal antibody in treatment rheumatoid arthritis (RA)

Embodiment 1.1-research design

Research colony by the age the representative group at least 18 years old patient (male or conceived, non-lactation period women) forms, its ACR1987 that satisfies RA reaches at least 3 months through revising criteria for classification.For guaranteeing to use the ACR standard detection to replying treatment, require qualified patient when randomization, to present activity RA, it is defined as joint 〉=6 of touching a tender spot in 28 joints, and swollen joint 〉=6 in 28 joints, and hSCRP〉10mg/L or ESR 〉=28mm/ the 1st hour (mm/h).Qualified candidate accepts that MTX treatment reaches at least 3 months and when selecting, through the stable dosage weekly of MTX (〉=7.5mg/ week-≤25mg/ week) at least 4 weeks for the treatment of.

To accept adult RA patient (n=237) mean randomization of methotrexate treatment to accept the subcutaneous injection of 25mg, 75mg, 150mg, 300mg Su Jin monoclonal antibody or placebo in every month.Include the patient's (18% to 22%) who before is exposed to biological preparation in all groups.Main terminal point is the patient's of Americanism damp disease association (ACR) 20 the ratio of reaching when the 16th week.When the 20th week (the 8th prescription on individual diagnosis), will the 0th when week randomization to the patient of placebo group or randomization to Su Jin monoclonal antibody group but reach the patient that ACR20 replys at the 16th Zhou Shiwei and divide into groups again, make it accept double-blind treatment until the 48th week, when the 52nd week, carry out final effect evaluation, and when the 60th week, follow up a case by regular visits to following when the 20th week, begin (Fig. 1):

The patient who carries out active treatment and reply continues its dosage;

No matter the disease liveness is how, with all placebo patients be converted to every around the active treatment of (every month) subcutaneous administration 150mg once;

Will be around every 25mg or the treatment of 75mg Su Jin monoclonal antibody and unresponsive all patients be converted to every around a subcutaneous administration 150mg;

Nonresponder in the 150mg group is converted to next maximum dose level-every subcutaneous administration 300mg all around;

Whether all patients in the 300mg group still accept its corresponding dosage can induce clinical response with the exposure that evaluation surpassed for 16 weeks in described patient.

Effect evaluation is ACR20,50,70 (people (1995) Arthritis Rheum such as Felson; 38 (6): 727-35) and DAS28 reply/alleviate (people (2003) Ann Rheum Dis such as Fransen; 62 (appendix 1): 10; People such as Prevoo (1995) Arthritis Rheum; 38 (1): 44-48).Primary efficacy variable was the 16th when week according to the improvement of the individual disease liveness of the ACR20 clinical response to treatment.By the time reaching the patient's of ACR20 ratio evaluation result in the 16th week.According to the ACR20 standard, if the patient has following situation, then it is considered as the respondent:

A) measure improvement at least 20% for following two:

The tenderness counting in 28 joints

The swelling counting in 28 joints; And

B) following 5 at least 3 improvement at least 20% measuring:

The patient is to RA Pain assessment (VAS100mm)

The patient is to the overall evaluation (VAS100mm) of disease liveness

The doctor is to the overall evaluation (VAS100mm) of disease liveness

Disability (the HAQ of patient self evaluation

Scoring)

Acute phase reactant (C-reactive protein [hsCRP] or erythrosedimentation speed (ESR))

Other are measured and comprise: ACR50 (5 are measured in B item (above) at least 3 improve 50% and swelling and tenderness joint counting improve 50%) and ACR70 (5 are measured in B item (above) at least 3 improve 70% and swelling and tenderness joint counting improve 70%).

DAS28 (disease liveness scoring-28) is measuring of the ripe RA disease liveness of setting up.Calculate this scoring by the complex mathematical formula, this mathematical formulae comprises that quantity (in 28 joints altogether), erythrosedimentation speed (ESR) or the hsCRP of tenderness joint and swollen joint and patient are to the overall evaluation (indicating by labelling 100mm line between splendid and extreme difference) of general health.The DAS28 scoring is controlled good disease less than 3.2 hints, and is alleviated less than 2.6 hints greater than 5.1 hint activity diseases.

Be to calculate DAS28, need be about the information of following disease variable:

Should use 28 joints to count to evaluate the quantity in swollen joint and tenderness joint (tenderness 28 and swelling 28).

Should be to measure erythrosedimentation speed (ESR) in mm/ hour.

Must obtain the patient's that measures at the visual simulation scale (VAS) of 100mm general health (GH) or overall disease liveness (the two all can be used for this purpose).

Use this data, can use following formula to calculate DAS28:

DAS28=0.56 * sqrt (touching a tender spot 28)+0.28 * sqrt (swelling 28)+0.70 * 1n (ESR)+0.014 * GH

When using following formula to calculate DAS or DAS28, can use C-reactive protein (CRP) to substitute ESR.CRP measures than the more direct inflammation of ESR, and it is more responsive to short term variations.The generation of CRP and the radioactivity of RA progress is relevant, and is regarded as at least the measure R A disease liveness equally effectively with ESR.Another advantage of measuring CRP is that the time of wait laboratory result is short and can use central laboratory under the situation of multicenter study.The following formula that uses CRP (mg/L) to calculate DAS28 provides the good estimation of initial DAS28 value in group's level.The tenderness counting in DAS28-4 (crp)=0.56 * sqrt (TJC28)+0.28 * sqrt (SJC28)+0.36 * ln (CRP+1)+0.014 * GH+0.96TJC28:28 joint; The swelling counting in SJC28:28 joint; The CRP:C-reactive protein; GH: based on the general health of 100mm visual simulation scale

Be the measuring of empirical tests of physical ability forfeiture and functional status.It has four dimensions: Disability, pain, drug side effect and money cost, but the back three is rarely used in the clinical trial.In this test, only use the Disability dimension.The Disability dimension is made up of 20 a plurality of options, and described project is about the difficulty of the general activity that carries out following 8 kinds of daily life: wear the clothes and wash and dress, get up, take food, walk, stretching, extension, Personal hygiene, grasping and activity.Individual select replying in the classification from " no hell and high water " to " can not do " four.This questionnaire is used in the RA outcome measurement rheumatism committee of ACR (ACR Rheumatology Committee on Outcome Measures in RA) suggestion in clinical trial.According to list in " HAQ PACK " from Stanford University, the developer's of California suggestion is right Mark.

Embodiment 1.2-statistical analysis

For test Su Jin monoclonal antibody is treated the superiority that group is better than placebo, based on utilizing treatment, center and baseline DAS28 to come each Su Jin monoclonal antibody treatment group of comparison with respect to the ACR20 respondent ratio (ratio) of placebo as the Logic Regression Models of co-variation amount.Use is analyzed DAS28-CRP with respect to the variation of baseline with treatment as main effects and at co-variation amount (ANCOVA, SAS PROC MIXED) the fixed-effect model analysis that co-variation amount center and baseline value are proofreaied and correct.The statistical test of the paired comparison Su Jin monoclonal antibody that is useful on treatment group and placebo all under bilateral 5% significant level, carry out.Last observation (LOCF) method of carrying down is used for the missing value of efficacy variable.Produce in time or present the figure that replys at the particular point in time until the 16th week (if suitably, or the 52nd week).It should be noted that for presenting for the result's in the 52nd week the figure, only be included in the patient's data that continues research the 24th week.

Complete analysis collection (FAS) is used for the report efficacy outcomes.FAS comprises all and has distributed the patient who studies medicine.Follow purpose treatment (ITT) principle, according to treatment and group (stratum) that patient when the randomization distributes the patient is analyzed.

The result in the 16th week of embodiment 1.3-

Demography and baseline characteristics are suitable in all groups.During the 16th week, when compare the ACR20 respondent more (being respectively 46.9%, 46.5% and 53.7%) (Fig. 2 A) in 75mg, 150mg and the 300mg Su Jin monoclonal antibody dosage group with 25mg Su Jin monoclonal antibody (34%) mutually with placebo (36.0%).Yet because the ACR20 in the placebo group significantly and inexplainably increases between the 12nd week (24%) and the 16th week (36%), described result does not reach significance,statistical.In 75mg to 300mg Su Jin monoclonal antibody treatment group, observe DAS28-CRP with respect to the minimizing (Fig. 5 A) of being correlated with clinically of placebo.When the 16th week, in 75mg to 300mg Su Jin monoclonal antibody group, change of serum C RP level significantly reduces (p=0.0012,0.0081 and 0.0241) (data not shown) with respect to placebo.In 16 weeks, the ACR50 of the Su Jin monoclonal antibody of 75mg to 300mg dosage and ACR70 demonstrate lasting bigger improving (Fig. 3 A and 4A) with respect to placebo.When the 16th week, compare with placebo, in 150mg to the 300mg group

Scoring with respect to the baseline decreased average about 4 times (Fig. 6 A).

The result in the 24th week of embodiment 1.4-

By the 24th week, 75mg to 300mg Su Jin monoclonal antibody treatment group keeps that ACR20 replys and DAS28CRP replys in further improvement between the 16th week and the 24th week.Between the 16th week and the 24th week, 75mg to 300mg Su Jin monoclonal antibody treatment group

Scoring is kept or is further reduced.75mg to 300mg ACR20 respondent treats group to the and presented in time in 24 weeks The early stage improvement of scoring.In the patient (part patient in 20th week increase dosage) of initial randomization to each dosage group, ACR50 replys the further 19%-24% of improvement (75mg), 21%-25% (150mg) and 19%-24% (300mg); In 75mg to 150mg group, observe the similar improvement that ACR70 replys.It may be noted that also randomization is replied increase to the patient's of placebo group ACR20/50/70 between the 16th week and the 24th week.When the 20th week, all be converted to 150mg Su Jin monoclonal antibody with accepting placebo all patients until the 16th week.

The result in the 52nd week of embodiment 1.5-

About Su Jin monoclonal antibody effect in time, once replied keeping it aspect ACR20 (Fig. 2 C), ACR50 (Fig. 3 B) and the ACR70 (Fig. 4 B) usually for respondent's patient in the 16th when week, and in the 150mg respondent organizes, observe the best and reply.To reply also be so in scoring for DAS28-CRP and HAQ, keeps described replying during in time to the 52nd week in the respondent in the 16th week, and also observe the best in 150mg respondent group and reply (Fig. 5 B, 6B).ACR20,50 and 70 during the 52nd week replys and is shown among Fig. 7, and the highest of all described parameters replied also in 150mg respondent group.

During the research beginning, the Biotherapeutics failure patient in each group is 18% to 22%.Formerly be exposed to biological preparation and use after the 20th week among the patient of 150mg Su Jin monoclonal antibody, when the 52nd week, 62% (in 13 8) reach ACR20, and 38% (in 13 5) reach ACR50 and 23% and reach ACR70.This proof, Su Jin monoclonal antibody can be treated the patient's of anti-TNF and the failure of other biological therapy for treating RA.

The analysis of embodiment 2:CAIN457F2201 medium or high risk RA patient subgroups

Embodiment 2.1-statistical analysis

When searching can be used for predicting RA patient to the index of replying of Su Jin monoclonal antibody treatment, but we utilize the CAIN457F2201 experimental data base data analysis two (referring to table 1) in four 2010ACR/EULAR standards of grading how to determine described standard (and whether) influence being replied the treatment of Su Jin monoclonal antibody.At first, serum analysis is to determine whether the patient is RF+ and/or anti-CCP+ (being ACPA+).Secondly, analyze the existence of acute phase reactant to determine whether the patient has high-caliber C-reactive protein (CRP) and/or high erythrosedimentation speed (ESR).

The summing-up statistics (binary is replied the meansigma methods of scaling of variables and continuous variable) of mainly utilizing in time and producing analyzes to observe replying until the 16th week (or for for patient of the 24th week continuation, until the 52nd week).Last observation (LOCF) method of carrying down is used for the missing value of efficacy variable.The data that generation presents in time or replys until the concrete time point in the 16th week (if suitably, or the 52nd week) time.It should be noted that for showing and only be included in the patient's data that continued in the 24th week for the result's in the 52nd week the data.

Among the embodiment 2.2-excessive risk RA patient to the analysis of replying of Su Jin monoclonal antibody

Patient's (i.e. " excessive risk RA patient ") the analysis of subgroup with " excessive risk " (based on high CRP and/or ESR and positive RF and/or ACPA) of progression of disease shows, the result compares with the CAIN457F2201 bulk testing, in the patient of Su Jin monoclonal antibody treatment, have promising result, and replying in the placebo group do not show similar increase trend.With regard to ACR20, in FAS, when the 16th week, in 75mg, 150mg, 390mg Su Jin monoclonal antibody and placebo, observe 46.9%, 46.5%, 53.7% and 36% respectively and reply (Fig. 2 A and table 6), and when the 16th week, in the excessive risk subgroup, observe 48.8%, 57.6%, 58.1% and 41.0% and reply (Fig. 2 B and table 6).Similarly, in the 16th week and the 52nd when week, in the excessive risk subgroup, observe and reply ratio and compare with FAS to some extent and increase, and its dependent variable (for example ACR50/70 (table 6), DAS28-CRP (table 7) and

(data not shown)) also be like this.

The summary that ACR20/50/70% when the 16th week and the 52nd week among FAS, excessive risk RA patient and the non-excessive risk RA patient and DAS28-CRP reply is provided in table 6 (ACR) and the table 7 (DAS28-CRP).The figure that ACR20/50/70% during the 16th week among excessive risk RA patient and the non-excessive risk RA patient and DAS28-CRP reply is described and is provided among Fig. 8 A and the 8B.

Table 6: the ACR in the 16th week and the 52nd week in FAS, excessive risk RA patient and non-excessive risk RA patient replys (LOCF)

Table 7: FAS, excessive risk RA patient and non-excessive risk RA patient change with respect to the intermediate value of the DAS28-ESR of baseline when the 16th week and 52 weeks.

Notice that for table 6 and 7, the data in the 52nd week are presented by the treatment of original allocation.When the 16th week, begin ACR20 nonresponder's (and all placebo patients) is carried out titration.18/45 " initially ", 25mg patient still accepted 25mg, and 27 patient dose rising titration (up-titrate) are to 150mg.Equally, 23/46 " initially ", 75mg patient still accepted 75mg, and 23 patient dose rising titration are to 150mg.20/43 " initially " 150mg patient still accepts 150mg and 23 patient dose rising titration to 300mg.All 44 " initially " placebo patients are converted to 150mg and all " initially " 300mg patients still accept 300mg.

As can comparing with non-excessive risk RA patient from table 6 and 7 and Fig. 8 A and 8B finding, excessive risk RA patient shows that usually the improvement that IL-17 is suppressed replys.ACR20% and ACR50% when comparing for the 16th week between excessive risk RA patient and the non-excessive risk RA patient reply (table 6 and Fig. 8 A), can observe in excessive risk RA patient the IL-17 by the Su Jin monoclonal antibody is suppressed to produce the dose response of replying.Observe similar dose response (table 7 and Fig. 8 B) in the DAS28-CRP scoring when the 16th and 52 weeks among the excessive risk RA patient.In addition, reply with observed ACR20% among the non-excessive risk RA patient and to compare, the ACR20% in the excessive risk RA patient subgroups replys and is improved (table 6 and Fig. 8 A) during the 16th week under being higher than all Su Jin monoclonal antibody dosage of 25mg.In addition, the ACR50/70% in the excessive risk RA patient of 150mg Su Jin monoclonal antibody treatment replied than the ACR50/70% in the non-excessive risk RA patient of identical Su Jin monoclonal antibody dosage treatment and replys height the 16th and 52 whens week.The DAS28-CRP of the Su Jin monoclonal antibody of all dosage observed similar results (table 7 and Fig. 8 B) in marking when the 16th when week, 150mg Su Jin monoclonal antibody was with the 52nd week.

Embodiment 3: the patient with rising baseline CRP benefits from the Su Jin monoclonal antibody

Embodiment 3.1-research design

Suffering from RA and comparing in the patient of the Su Jin of various dose monoclonal antibody treatment dosage-response relation that DAS28 and ACR reply when all by baseline high sensitivity (hs) CRP proficiency assessment the 16th with placebo.

As mentioned before, in research CAIN457F2201, make adult RA patient (n=237) randomization of accepting the methotrexate treatment to accept the subcutaneous injection of 25mg, 75mg, 150mg, 300mg Su Jin monoclonal antibody or placebo in every month.By different baseline hsCRP levels (〉=0mg/L, 〉=10mg/L, 〉=20mg/L and 〉=30mg/L) evaluation the 16th when week DAS28 and the ACR dose relationship of replying.

Embodiment 3.2-result

Demography and baseline characteristic are suitable in all groups.In the patient group that accepts 75mg, 150mg, 300mg Su Jin monoclonal antibody, reduce fast as far back as namely observing DAS28-CRP the 2nd week.By the 12nd week, described patient compares with those persons that accept the placebo and reaches〉1.2 significant DAS28 clinically reduces (P＜0.05).Described replying continued until the 16th week (table 8).As table 8 and seen in fig. 9, based on baseline hsCRP level, the 16th when week, compare with placebo or 25mg and 75mg Su Jin monoclonal antibody group, DAS28-CRP, the ACR20 of 150mg and 300mg Su Jin monoclonal antibody dosage group and ACR50 reply the dose dependent relation that exists.Until the 20th week, security feature and the placebo of Su Jin monoclonal antibody are suitable.The seriousness of most of AE is slight or moderate and do not cause studying medicine and stop.

Show 8-with respect to the CRP of baseline place level, dosage-response relation of DAS28-CRP, ACR20 and ACR50 during the 16th week.DAS28-CRP, ACR20, and the ACR50 data provided by intermediate value; N: patient's quantity.“0”=0mg/ml，“10”=10mg/ml，“20”=20mg/ml，“30”=30mg/ml。

The result shows that the Su Jin monoclonal antibody can reduce the disease liveness fast, accepts 150mg or 300mg and as is had by baseline hsCRP level proof among the patient of high inflammatory burden and observe greatest improvement at those.This prompting Su Jin monoclonal antibody is given RA patient benefit, comprises that those have the patient of the excessive risk factor that causes PD.

Embodiment 4: modeling and simulation: the design of rheumatic arthritis induction scheme

Relation between the PK/PD method of use description longitudinal data is replied Su Jin monoclonal antibody dosage/scheme, Su Jin monoclonal antibody plasma concentration and ACR20 is carried out modeling.The design that described model was tested for the III phase of auxiliary Su Jin monoclonal antibody treatment rheumatoid arthritis.

Embodiment 4.1-method

The dynamic (dynamical) modeling of Su Jin monoclonal antibody medicine

For pharmacokinetics (PK) model (Figure 10), compile the data of different clinical researches (CAIN457A1101, CAIN457A2101, CAIN457A2102, CAIN457A2103, CAIN457A2104, CAIN457A2206, CAIN457A2208, CAIN457A2209 and CAIN457F2201).Colony's method with two Room models is used for describing Su Jin monoclonal antibody PK.Estimation colony's parameter and interindividual variation thereof.Described parameter is: volume of distribution V1=2.96L and V2=2.52L, and the one-level clearance rate CL=0.169L/ day of first volume, exchange coefficient Q=0.784L/ day between the chamber, and the absorbance of subcutaneous administration and absolute bioavailability are respectively KA=0.192l/ day and F=76%.Body weight is differentiated and is the co-variation amount about Su Jin monoclonal antibody clearance rate and volume.

The modeling that the ACR20 respondent leads in placebo and Su Jin monoclonal antibody treatment group

For the ACR20 modeling data (table 9) that methotrexate is replied not enough patient, use the data of two clinical researches (CAIN457A2101 and CAIN457F2201).Use placebo and through concentration-respondent's probability method for the treatment of group ACR20 respondent ratio is carried out modeling.Suppose placebo and reply the ratio monotonic increase until the 16th week through the ACR20 for the treatment of group.The monotonic increase curve depends on the logarithm of time and the square root of Su Jin monoclonal antibody concentration.Carry out modeling at placebo and the ACR20 (LoCF) that observes during to the 4th week (the 29th day), the 8th week (the 57th day), the 12nd week (the 86th day) and the 16th week (the 113rd day) with two steps through treatment group.

The ACR20 time response model of placebo group

J name patient in the placebo group is at time t _iThe ACR20 that observes when (i=1,2,3,4 the 4th, 8,12 and 16 weeks of expression) is write as:

ACR20 _0j(t _i)～binomial (1, p ₀(t _i))

Logit(p ₀(t _i))=α+βlog(t _i)/log(t ₄)。

Therefore, the decilog (logit) that the ACR20 in the 16th when week placebo group replys ratio is that alpha+beta and 0 o'clock time, it was-∞ that it has the probability of replying constantly the time corresponding to 0 is 0 situation.

ACR20 time response model through the group that the Su Jin monoclonal antibody is treated

J name patient in Su Jin monoclonal antibody treatment group is at time t _iThe time ACR20 that observes write as:

ACR20 _j(t _j)～binomial (1, p (t _i))

Logit (p (t _i))=Logit (p ₀(t _i))+γ (t _i) h (conc _j(t _i)), wherein h () is the square root of individual model prediction concentration.Herein, γ is at time t _iThe time ACR20 respondent ratio to the change of sensitivity of concentration.

γ(ti)=γ ₀log(t _i)/log(t ₄)。

Therefore, by γ (t _i) h (conc _j(t _i)) effect of Su Jin monoclonal antibody described.Identical with the placebo time effect, functional form γ is through being chosen as the logarithm of research natural law, and in other words, the accumulation of supposing to represent with h (conc) is than number (proportional odd).

Use general estimation equation method to assess and suppose that association has Composite Symmetry in the patient that observed ACR20 replys.

Embodiment 4.2-result

Embodiment 4.2.1-PK modeling result

As shown in Figure 10, this model prediction is used intravenous or subcutaneous induction scheme to compare with no induction scheme and can be reached more Gao Sujin monoclonal antibody plasma concentration.In addition, this model further predicts, uses the induction scheme of the comparable use of induction scheme 300mg Su Jin monoclonal antibody of subcutaneous delivery when the 0th, 1,2,3 and 4 weeks of the 10mg/kg Su Jin monoclonal antibody that intravenous is sent when the 0th, 2 and 4 weeks that higher Su Jin monoclonal antibody plasma concentration (and more rapid rate under) is provided.Comparing with the dosage regimen of no induction scheme through the subcutaneous of modeling and intravenous induction scheme provides improved and replys.

Embodiment 4.2.4-ACR20 analog result

The result of ACR20 respondent modeling is provided in the table 9.The ACR20 simulation and forecast is compared with no induction scheme (35%), uses intravenous (63%) or subcutaneous (57%) induction scheme can reach bigger ACR20 and replys ratio.In addition, this model is further predicted, uses the induction scheme of the comparable use of induction scheme 300mg Su Jin monoclonal antibody of subcutaneous delivery when the 0th, 1,2,3 and 4 weeks of the 10mg/kg Su Jin monoclonal antibody that intravenous is sent when the 0th, 2 and 4 weeks to provide bigger ACR20 to reply ratio.Comparing with the dosage regimen of no induction scheme through the subcutaneous of modeling and intravenous induction scheme provides improved and replys.

The ACR20 respondent ratio of table 9-simulation.

Embodiment 5: the Su Jin monoclonal antibody shows good safety and effect in the treatment of the mandatory spondylitis of activity

Example 5,1-research design CAIN457A2209

CAIN457A2209 be suffer from the II phase of moderate to the patient of serious AS, multicenter, at random, double blinding, parallel group, the research of placebo Proof of Concept.Research colony is to be 18 to 65 years old patient at the age, it has AS according to modified New York standard diagnostics, back pain and night pain scores 〉=4 (0 to 10 scale divisions, BASDAI scoring 〉=4 (0 to 10 scale division, and at least a NSAID current or that before used at least 3 months with maximum recommended dosage replied deficiency.The patient of previous use TNF-≤alpha blocker can be recruited through suitable medicament elution after date.During studying, make the patient continue to accept simultaneously the treatment of NSAIDS, methotrexate (MTX), sulfasalazine (sulphasalazine) and the prednisolone of consistent dose.Yet eliminating has the patient of the sign of activity tuberculosis.

Make 30 (30) patients give the infusion of two doses of 10mg/kg intravenous Su Jin monoclonal antibodies (AIN457) or intravenous placebo at interval 3 weeks with acceptance with 4:1 ratio randomization.To follow the tracks of patient's safety until the 28th week.The 6th all ASAS20 that carry out AIN457 and placebo reply Bayes (Bayesian) analysis of ratio.The distribution in advance of replying ratio is appointed as the β distribution and is supposed that observed respondent's quantity is binomial distribution in each group.The prediction distribution that the placebo that use is analyzed (meta-analysis) from 8 randomization placebo-controlled trial integrations of the anti-TNF alpha of AS treatment is replied ratio is replied the distribution in advance of ratio as placebo.This distributes to be equivalent in advance and observe 11 respondents (namely replying ratio is 26%) in 43 patient.Weak distribution is in advance replied ratio (being equivalent to 0.5 respondent in 1.5) as activity.

When being the 6th week, reaches at main terminal point (ASAS) 20 patients' that reply ratio of international ankylosing spondylitis association's evaluation (Assessment of Spondylo Arthritisinternational Society).

Embodiment 5.2-result

Demography and baseline characteristic are suitable between each group.Through average (SD) BASDAI of baseline of the patient of Su Jin monoclonal antibody treatment be 7.1 (1.4) and the patient of placebo treatment be 7.2 (1.8).2 patients that accept 3 patients of placebo and accept AIN457 were stopping research before main terminal point, this mainly is because therapeutic effect is unsatisfactory.Its efficacy data is unavailable owing to violate the agreement behind the randomization for 1 patient.When the 6th week, entering among 23 Su Jin monoclonal antibodies treatment patients of efficiency analysis 14 reaches ASAS20 and replys, and reach (61% to 17%, the probability of positive treatment difference=99.8%, confidence interval 11.5%, 56.3%) to 1 in 6 placebo-treated patients.It is respectively 30% and 35% that Su Jin monoclonal antibody treatment patient's ASAS40 and ASAS5/6 reply, and average (scope) BASDAI variation is-1.8 (5.6 to 0.8).In most of ASAS20 respondents, the Su Jin monoclonal antibody is induced in the treatment in a week and is replied.Pharmacokinetic properties is as expecting at IgG1mAb and suitable with the Su Jin monoclonal antibody that gives for other indications.

The main terminal point of this research is reached, because the Su Jin monoclonal antibody induces remarkable higher ASAS20 to reply than placebo when the 6th week.Early stage safety signal not to be noted in this research colony.Data in mid-term provided herein show that the Su Jin monoclonal antibody can be used for treating the activity ankylosing spondylitis.

Embodiment 6: the Su Jin monoclonal antibody alleviates the S﹠S of arthritic psoriasis in 24 all multicenters, double blinding, randomization, placebo-controlled trial

Embodiment 6.1-research design and demography

Distribute 42 patients that suffer from the arthritic psoriasis (PsA) that satisfies the CASPAR standard with 2:1, make it accept Su Jin monoclonal antibody (10mg/kg) or the placebo injection that gives in three weeks of two minor ticks.When being the 6th week, main effect terminal point compares activity ACR20 respondent's ratio (one-sided p value＜0.1) with the placebo receiver.According to scheme, do not impute missing data (release value is pressed missing value and handled).

25 (89%) accepts the patient of Su Jin monoclonal antibody and patient that 10 (71%) accepts placebo finishes this research.Owing to violate the agreement, 5 patients are excluded out efficiency analysis (accept Su Jin monoclonal antibody and 1 for 4 and accept placebo).3 (11%) accepts the patient of Su Jin monoclonal antibody and patient that 4 (29%) accepts placebo does not stop too early because having effect or recalling letter of consent.Balance is at demography and the baseline characteristic of age, sex and parameter between each group, comprises average (SD) SJC (the Su Jin monoclonal antibody is to placebo): 8.3 (5.6) to 9.5 (5.4), TJC23.5 (19.4) to 22.6 (11.0), DAS284.8 (1.2) to 4.8 (1.2), MASES3.0 (4.1) is to 3.4 (2.3).The coexistence psoriasis, TNFi exposes and has 23 (98%), 11 (46%) and 21 (88%) with the patient of DMARDS administering drug combinations in the patient who accepts the Su Jin monoclonal antibody and accepting 11 (89%) of existence, 5 (38%) and 10 (70%) among the patient of placebo in advance.

Embodiment 6.2-result

It is 39% (9/23) that the ACR20 that the time accepts the patient of Su Jin monoclonal antibody the 6th week replys ratio, and what accept placebo is 23% (3/13) (P=0.27).The time utilizing the Su Jin monoclonal antibody that the ACR20 of placebo is replied ratio in the 12nd week is respectively 39% (9/23) to 15% (2/13), and is 43% (10/23) to 18% (2/11) during the 28th week.The time accepting the Su Jin monoclonal antibody the 6th week, the ACR50 of placebo and ACR70 are replied ratio is respectively 17% pair 8% and 9% pair 0%.Observation accept the CRP that Su Jin monoclonal antibody the 6th compares with baseline during week reduce (baseline intermediate value [scope] is 5.0[0.3,43.0] 3.0[0.2 during to the 6th week, 15.2], but do not accept placebo (baseline (and 3.9[1.3,39.7] 5.0[0.8 during to the 6th week, 29.6]).Observe similar minimizing at ESR, and acute stage parameter minimizing be maintained to for the 28th week.The overall rate of the adverse events (AE) of Su Jin monoclonal antibody contrast placebo is suitable: 26 (94%) to 11 (79%).A kind of serious adverse events (cellulitis of hand) takes place when accepting the Su Jin monoclonal antibody, and researcher does not suspect that it is relevant with the research medicine.The serious AE of report seven examples in 4 Su Jin monoclonal antibody patients (tendon rupture/canalis carpi syndrome/cellulitis, obesity, fall, breast carcinoma [before administration, make a definite diagnosis, it is recruited to constitute violate the agreement]) and the serious AE (polyarthritis) of placebo patients report 1 example.16 (57%) accepts the patient of Su Jin monoclonal antibody and patient that 7 (50%) accepts placebo reports infection.

The security feature of Su Jin monoclonal antibody is favourable generally.Although main terminal point does not reach, quite the patient of vast scale shows until the 28th all clinical scores and the quick and Continual Improvement of acute stage parameter.Trend support towards useful clinical effectiveness designs clinical trial to evaluate the idea of clinical usefulness.

The pharmacokinetics information (PK) of embodiment 7-Su Jin monoclonal antibody

Based on the data (comprising the data of discussing above-described embodiment) that obtain from various researchs, obtain the following PK information (table 10) of Su Jin monoclonal antibody.

Table 10: the experiment of Su Jin monoclonal antibody and aids drug kinetics value

In addition, determined that the Su Jin monoclonal antibody has about 7 to 8 days T _MaxAnd about 30 days elimination half-life.This PK information can be used for being designed for the different dosing regimes for the treatment of of arthritis (for example, RA, for example excessive risk RA).Use this PK information can send with embodiment in used dosage various dose the IL-17 antagonist (for example, IL-17 binding molecule (IL-17 antibody for example, Su Jin monoclonal antibody for example) or IL-17 receptors bind molecule (for example IL-17 receptor antibody)) or send with embodiment in used same dose, but when the time point different with the time point among the embodiment, provide.By keeping identical PK characteristic, even dosage regimen or dosage are variable, estimate that those skilled in the art also can be with the IL-17 antagonist (for example, IL-17 binding molecule (IL-17 antibody for example, Su Jin monoclonal antibody for example) or IL-17 receptors bind molecule (for example IL-17 receptor antibody)) be used for the treatment of arthritis, comprise treatment excessive risk RA patient.

Embodiment 8: the pharmaceutical composition/medicine that comprises the IL-17 antagonist

Bring into use the preparation research of Su Jin monoclonal antibody medicine, its objective is the high-intensity product of research and development, the bottle that for example has the unit dose of 150mg Su Jin monoclonal antibody.Four kinds based on the preparation of sucrose place truly with the combination of different stabilizing agent (mannitol, glycine, arginine monohydrochloride), stability experiment under acceleration and the stressed condition reaches 12 months (table 11).

Table 12 – lyophilizing cycling condition

The aggregation that in preparation, records via the residual moisture of measuring cake outward appearance, pH, reprovision time, recorded by Ka Er-Fei Xier (Karl Fischer), by SE-HPLC and catabolite, the impurity that under reducing condition, is recorded by SDS-PAGE, the mean molecule quantity that is recorded by LLS, the catabolite that is recorded by RP-HPLC and the theoretical active monitoring Su Jin monoclonal antibody stability that is recorded by cystamine CEX.With water for injection 3:1 reprovision after initial time point measure osmotic pressure and, viscosity (table 13).

Table 13 – gives osmotic pressure and the viscosity of customization agent

Osmotic pressure value is fully in the PhEur that is higher than 240mOsm/Kg accepts the restriction of standard and in the tolerance interval of viscosity results at 10mPa * s.Indicate the difference of no purity characteristic between the preparation of concrete different stabilizers at 12 months stability datas of the sample that stores under the true temperature condition.When storing, the outward appearance of lyophilized products cake and pH do not have significant difference between each preparation, yet the preparation that contains mannitol is compared the longer a little reprovision time of demonstration (6 minutes to 3 minutes) with other preparations.Moisture increases to 0.4% from about 0.2%, with preparation irrelevant (data not shown).The aggregation that is recorded by SEHPLC increases to 1.4% from 0.9%, and catabolite is lower than quantitative restriction (data not shown).AIN457 mean molecule quantity after storage does not still change for about 155kDa.The initial content of total RP-HPLC material is about 8.5% to 10%, enlarges markedly to 14.6% (data not shown) after storing 12 months down at 5 ℃.Should emphasize that described content reaches the platform section from storing 1 month.The AIN457 activity that is recorded by cystamine CEX remains in 98% to 99% (data not shown).Accelerate and stress temperature conditions under 6 months stability datas of the sample that stores disclose, with regard to after storing with regard to the generation of long reprovision time (6 minutes to 3 minutes), the highest gathering product content and RP-HPLC catabolite, the preparation that contains sucrose+mannitol is obviously different with other preparations.When storing, the outward appearance of lyophilized products cake and pH do not have significant difference between each preparation.40 ℃ down store 6 months after, moisture increases to 0.6% to 0.7% from about 0.2%, and forms irrelevant (data not shown).The preparation that contains sucrose shows than containing the lower slightly aggregation extent of mannitol, glycine and arginic other preparations (recording 5.2% pair 5.8% to 6.8% by SE-HPLC) in addition.For all preparations, catabolite all is lower than quantitative limit value (data not shown).The AIN457 mean molecule quantity keeps about 160kDa constant after storing 6 months under 40 ℃.40 ℃ down store 6 months after, based on the preparation of independent sucrose or total RP-HPLC content of degradation products (reaching 31.0% and 31.4%) with preparation of arginine monohydrochloride a little less than other two kinds of preparations (32.8% and 35.6%) (data not shown).The AIN457 activity that is recorded by cystamine CEX remains on 94% to 95% (data not shown).

Result of study shows, the preparation based on 90mM sucrose that was present in 10mM histidine, 0.02% polysorbate80 (pH5.8) with 50mg/mL before lyophilizing is the optimum candidate of listing preparation, and the listing preparation comprises 150mg/mL AIN457,30mM L-histidine buffer (pH5.8), 270mM sucrose and 0.06% polysorbate80 after with 1.0mL water for injection 3:1 reprovision.

Claims

1. the method for a treatment rheumatoid arthritis (RA) comprises to the IL-17 antagonist of excessive risk RA patient administering therapeutic effective dose.

2. the method for a treatment rheumatoid arthritis (RA) comprises

A) be excessive risk RA patient and select this patient to treat based on the patient; And

B) to the IL-17 antagonist of this patient's administering therapeutic effective dose.

3. method as claimed in claim 1 or 2, wherein said step of applying comprises IL-17 antagonist from 3 doses of about 10mg/kg to described patient's intravenous that use, uses potion week about.

4. method as claimed in claim 1 or 2, wherein said step of applying comprise this IL-17 antagonist of the dosage to the about 75mg of described patient's subcutaneous administration to about 300mg, use this dosage of potion in every month.

5. method as claimed in claim 1 or 2, wherein said step of applying comprises:

A) during induction scheme, use this IL-17 antagonist to this excessive risk RA patient; And

B) after this during Concept of Maintenance, use this IL-17 antagonist to this patient.

6. method as claimed in claim 5, wherein this induction scheme comprises this IL-17 antagonist from three doses of about 10mg/kg dosage to this patient's intravenous that use.

7. method as claimed in claim 6 is wherein sent first dosage of about 10mg/kg during the 0th week, send second dosage of about 10mg/kg during the 2nd week, and send the 3rd dosage of about 10mg/kg during the 4th week.

8. method as claimed in claim 5, wherein this Concept of Maintenance comprises this IL-17 antagonist to the about 75mg of this patient's subcutaneous administration to about 300mg.

9. method as claimed in claim 8, wherein this Concept of Maintenance comprised every month twice, every month, per two months or every three months this IL-17 antagonist to the about 75mg of this patient's subcutaneous administration to about 300mg.

10. method as claimed in claim 9, wherein this Concept of Maintenance begins during being included in for the 8th week, every month twice, every month, per two months or every three months this IL-17 antagonist to the about 75mg of this patient's subcutaneous administration to about 150mg.

11. method as claimed in claim 10, wherein this Concept of Maintenance begins during being included in for the 8th week, every month this IL-17 antagonist to the about 75mg of this patient's subcutaneous administration or about 150mg.

12. as the described method of above each claim, wherein this excessive risk RA patient:

A) be rheumatoid factor seropositivity (RF+), anti-citrulline protein antibodies seropositivity (ACPA+), or be RF+ and ACPA+ simultaneously; And

B) have high C-reactive protein (CRP) level, high erythrosedimentation speed (ESR) or high CRP level and high ESR the two.

13. method as claimed in claim 12, wherein as measured by hsCRP, this high CRP level is 〉=10mg/L.

14. method as claimed in claim 12, wherein this high ESR is 〉=28mm/h.

15. the method for a treatment rheumatoid arthritis (RA) comprises to the IL-17 antagonist of patient's administering therapeutic effective dose, prerequisite is that this patient treats based on following standard is selected:

A) be RF+, ACPA+ or RF+ and ACPA+ the two; And

B) have high CRP level, high ESR or have high CRP level simultaneously and high ESR the two.

16. method as claimed in claim 15, wherein said step of applying comprises:

A) during induction scheme, use this IL-17 antagonist to this patient; And

17. method as claimed in claim 16, wherein this induction scheme comprises this IL-17 antagonist from three doses of about 10mg/kg dosage to this patient that use.

18. method as claimed in claim 17 is wherein sent first dosage of about 10mg/kg during the 0th week, send second dosage of about 10mg/kg during the 2nd week, and send the 3rd dosage of about 10mg/kg during the 4th week.

19. method as claimed in claim 16, wherein this Concept of Maintenance comprises to this patient and uses about 75mg to this IL-17 antagonist of about 300mg.

20. method as claimed in claim 19, wherein this Concept of Maintenance comprised every month twice, every month, per two months or every three months this IL-17 antagonist to the about 75mg of this patient's subcutaneous administration to about 300mg.

21. method as claimed in claim 20, wherein this Concept of Maintenance begins during being included in for the 8th week, every month twice, every month, per two months or every three months this IL-17 antagonist to the about 75mg of this patient's subcutaneous administration to about 150mg.

22. method as claimed in claim 21, wherein this Concept of Maintenance begins during being included in for the 8th week, every month this IL-17 antagonist to the about 75mg of this patient's subcutaneous administration or about 150mg.

23. as the described method of above each claim, wherein before using this IL-17 antagonist, before through the RA treatment, this treatment comprises used at least a moist medicine of following wind resistance that is selected to this patient: immunosuppressant, the moist medicine of wind resistance (DMARD) of alleviating disease, pain control medicine, steroid, non-steroidal anti-inflammatory drug thing (NSAID), cytokine antagonist, bone anabolic agent, anti-bone resorption agent and combination thereof.

24. method as claimed in claim 23, wherein before using this IL-17 antagonist, this patient replys deficiency, treatment failure to the treatment of using DMARD, TNF alpha-2 antagonists or methotrexate or does not tolerate.

25. as the described method of above each claim, wherein at least a moist medicine of following wind resistance that is selected from of the other administering therapeutic effective dose of this patient: immunosuppressant, DMARD, pain control medicine, steroid, NSAID, cytokine antagonist, bone anabolic agent, anti-bone resorption agent and combination thereof.

26. the method for a treatment rheumatoid arthritis (RA) comprising:

A) use three doses of IL-17 antagonisies with the dosage of about 10mg/kg to excessive risk RA patient, each agent in these three doses is sent week about; And

B) after this, the intravenous of hanging oneself is sent a beginning in month behind the 3rd dosage, uses the extremely IL-17 antagonist of about 150mg of about 75mg to this patient in every month.

27. the therapeutic scheme of a treatment rheumatoid arthritis (RA) comprising:

A) suffer from the patient of RA according to following Standard Selection:

I. this patient be RF+, ACPA+ or RF+ and ACPA+ the two; And

Ii. this patient have high CRP level, high ESR or have high CRP level simultaneously and high ESR the two; And

B) use this IL-17 antagonisies of three doses of about 10mg/kg dosage to this patient, during the 0th week, send first dosage of about 10mg/kg, during the 2nd week, send second dosage of about 10mg/kg, and during the 4th week, send the 3rd dosage of about 10mg/kg; And

C) after this begin during the 8th week, every month twice, every month, per two months or every three months are used about 75mg to this IL-17 antagonist of about 150mg to this patient.

28. the method for a treatment rheumatoid arthritis (RA) comprising:

A) the following project of analysis patient's sample:

I. rheumatoid factor (RF), anti-citrulline protein antibodies (ACPA) or RF and ACPA; And

Ii.C-reactive protein (CRP), erythrosedimentation speed (ESR) or CRP and ESR the two; And

B) if this patient is RF+, ACPA+ or RF+ and ACPA+ and this patient to have high CRP level, high ESR or have high CRP level and high ESR simultaneously, then use this IL-17 antagonist to this patient.

29. a definite RA patient will produce the method for the probability of replying to the IL-17 antagonist for treating, comprise the following project of the sample of analyzing the patient:

A) rheumatoid factor (RF), anti-citrulline protein antibodies (ACPA) or RF and ACPA; And

B) C-reactive protein (CRP), erythrosedimentation speed (ESR) or CRP and ESR the two;

Have high CRP level, high ESR or have high CRP level and high ESR simultaneously if this patient is RF+, ACPA+ or RF+ and ACPA+ and this patient, then this patient may produce the RA treatment of using this IL-17 antagonist and reply.

30. an IL-17 antagonist that is used for the treatment of rheumatoid arthritis (RA) is characterized in that using this IL-17 antagonist to excessive risk RA patient.

31. an IL-17 antagonist that is used for the treatment of rheumatoid arthritis (RA) is characterized in that to based on this patient being excessive risk RA patient and select its patient who treats is used this IL-17 antagonist.

32. as the IL-17 antagonist of purposes as described in claim 30 or 31, wherein this IL-17 antagonist is to use three times with the dosage of about 10mg/kg, uses this dosage of potion week about.

33. as the IL-17 antagonist of purposes as described in claim 30 or 31, wherein this IL-17 antagonist is to use to the dosage of about 300mg with about 75mg, uses this dosage of potion in every month.

34. as the IL-17 antagonist of purposes as described in claim 30 or 31, wherein during induction scheme and Concept of Maintenance after this to there being this patient who needs to use this IL-17 antagonist.

35. as the IL-17 antagonist of purposes as described in the claim 34, wherein this induction scheme comprises this IL-17 antagonist from three doses of about 10mg/kg dosage to this patient's intravenous that use.

36. as the IL-17 antagonist of purposes as described in the claim 35, wherein during the 0th week, send first dosage of about 10mg/kg, during the 2nd week, send second dosage of about 10mg/kg, and during the 4th week, send the 3rd dosage of about 10mg/kg.

37. as the IL-17 antagonist of purposes as described in the claim 34, wherein this Concept of Maintenance comprises this IL-17 antagonist to the about 75mg of this patient's subcutaneous administration to about 300mg.

38. as the IL-17 antagonist of purposes as described in the claim 37, wherein this Concept of Maintenance begins during being included in for the 8th week, every month twice, every month, per two months or every three months this IL-17 antagonist to the about 75mg of this patient's subcutaneous administration to about 300mg.

39. as the IL-17 antagonist of purposes as described in the claim 38, wherein this Concept of Maintenance begins during being included in for the 8th week, every month twice, every month, per two months or every three months this IL-17 antagonist to the about 75mg of this patient's subcutaneous administration to about 150mg.

40. as the method for claim 39, wherein this Concept of Maintenance begins during being included in for the 8th week, every month this IL-17 antagonist to the about 75mg of this patient's subcutaneous administration or about 150mg.

41. as the IL-17 antagonist of purposes, wherein this excessive risk RA patient as described in each in the claim 30 to 40:

42. as the IL-17 antagonist of purposes as described in the claim 41, wherein as measured by hsCRP, this high CRP level is 〉=10mg/L.

43. as the IL-17 antagonist of purposes as described in the claim 41, wherein this high ESR is 〉=28mm/h.

44. an IL-17 antagonist that is used for the treatment of rheumatoid arthritis (RA) is characterized in that and will use this IL-17 antagonist to the patient, prerequisite is that this patient is based on following standard and is selected and treats:

A) be RF+, ACPA+ or RF+ and ACPA+ the two; And

45. the IL-17 antagonist as purposes as described in the claim 44 is characterized in that using this IL-17 antagonist to this patient during induction scheme, and uses this IL-17 antagonist to this patient then during Concept of Maintenance.

46. as the IL-17 antagonist of purposes as described in the claim 45, wherein this induction scheme comprises this IL-17 antagonist from three doses of about 10mg/kg dosage to this patient that use.

47. as the IL-17 antagonist of purposes as described in the claim 46, wherein during the 0th week, send first dosage of about 10mg/kg, during the 2nd week, send second dosage of about 10mg/kg, and during the 4th week, send the 3rd dosage of about 10mg/kg.

48. as the IL-17 antagonist of purposes as described in the claim 45, wherein this Concept of Maintenance comprises to this patient and uses about 75mg to this IL-17 antagonist of about 300mg.

49. as the IL-17 antagonist of purposes as described in the claim 48, wherein this Concept of Maintenance comprised every month twice, every month, per two months or every three months this IL-17 antagonist to the about 75mg of this patient's subcutaneous administration to about 300mg.

50. as the IL-17 antagonist of purposes as described in the claim 49, wherein this Concept of Maintenance begins during being included in for the 8th week, every month twice, every month, per two months or every three months this IL-17 antagonist to the about 75mg of this patient's subcutaneous administration to about 150mg.

51. purposes as claimed in claim 50, wherein this Concept of Maintenance begins during being included in for the 8th week, every month this IL-17 antagonist to the about 75mg of this patient's subcutaneous administration or about 150mg.

52. as the IL-17 antagonist of purposes as described in each among the claim 30-51, wherein before using this IL-17 antagonist, this patient had before accepted the RA treatment, and this treatment comprises uses at least a moist medicine of following wind resistance that is selected from: immunosuppressant, the moist medicine of wind resistance (DMARD) of alleviating disease, pain control medicine, steroid, non-steroidal anti-inflammatory drug (NSAID), cytokine antagonist, bone anabolic agent, anti-bone resorption agent and combination thereof.

53. as the IL-17 antagonist of purposes as described in the claim 53, wherein before using this IL-17 antagonist, this patient replys deficiency, treatment failure to the treatment of using DMARD, TNF alpha-2 antagonists or methotrexate or does not tolerate.

54. as the IL-17 antagonist of purposes as described in each among the claim 30-51, wherein at least a moist medicine of following wind resistance that is selected from of the other administering therapeutic effective dose of this patient: immunosuppressant, DMARD, pain control medicine, steroid, NSAID, cytokine antagonist, bone anabolic agent, anti-bone resorption agent and combination thereof.

55. an IL-17 antagonist that is used for the treatment of rheumatoid arthritis (RA) is characterized in that this IL-17 antagonist:

A) use three times to excessive risk RA patient with the dosage of about 10mg/kg, these three dosage are to send potion week about; And

B) thereafter, the intravenous of hanging oneself is sent a beginning in month behind the 3rd dosage, every month with about 75mg extremely the dosage of about 150mg use to this patient.

56. an IL-17 antagonist that is used for the treatment of rheumatoid arthritis (RA) is characterized in that:

A) the following project of analysis patient sample:

IiC-reactive protein (CRP), erythrosedimentation speed (ESR) or CRP and ESR the two; And

57.IL-17 antagonist is characterized in that using this IL-17 antagonist to excessive risk RA patient for the preparation of the purposes in the medicine for the treatment of RA.

58.IL-17 antagonist is characterized in that using this IL-17 antagonist to excessive risk RA patient during induction scheme and Concept of Maintenance after this for the preparation of the purposes in the medicine for the treatment of RA.

59. a pharmaceutical composition that is used for the treatment of RA, it comprises the IL-17 antagonist as active ingredient, wherein uses this IL-17 antagonist to excessive risk RA patient.

60. a pharmaceutical composition that is used for the treatment of RA, it comprises the IL-17 antagonist as active ingredient, wherein uses this IL-17 antagonist to excessive risk RA patient during induction scheme and Concept of Maintenance after this.

61. as the pharmaceutical composition of claim 57 or 58 described purposes or claim 59 or 60, wherein this excessive risk RA patient:

B) have high C-reactive protein (CRP) level, high erythrosedimentation speed (ESR) or have high CRP level simultaneously and high ESR the two.

62. a therapeutic scheme for the treatment of RA, it comprises:

A) select excessive risk RA patient;

B) during the 0th, 2 and 4 weeks, use about 10mg/kg IL-17 antagonist to this patient; And

C) thereafter in the 8th week beginning, used extremely this IL-17 antagonist of about 150mg of about 75mg to this patient in every month.

63. a method for the treatment of RA patient or excessive risk RA patient comprises:

A) use the IL-17 binding molecule to patient that these needs are arranged during induction scheme, this induction scheme provides the average maximal plasma concentration (C of this IL-17 binding molecule of about 360 μ g/ml _Max); And

B) thereafter, use this IL-17 binding molecule to this patient during Concept of Maintenance, this Concept of Maintenance provides:

I) between the average steady state valley concentration of about 8 μ g/ml to this IL-17 binding molecule between about 30 μ g/ml; And/or

Ii) about 331mg * day/L average A UC τ to the stable state of about 1323mg * day/L.

64. an IL-17 binding molecule that is used for the treatment of RA patient or excessive risk RA patient is characterized in that this IL-17 binding molecule:

A) use to this patient during induction scheme, this induction scheme provides the average maximal plasma concentration (C of this IL-17 binding molecule of about 360 μ g/ml _Max); And

B) thereafter, use to this patient during Concept of Maintenance, this Concept of Maintenance provides:

65. as the described method of claim 63 or the described purposes of claim 64, wherein this induction scheme this valley concentration of keeping this IL-17 binding molecule in the periods in 10 weeks is higher than 80 μ g/ml.

66. as the described method of claim 63 or the described purposes of claim 64, wherein this Concept of Maintenance provides about 8 μ g/ml average steady state valley concentration to this IL-17 binding molecule of about 17 μ g/ml.

67. as the described method of claim 66 or purposes, wherein this Concept of Maintenance provides the average steady state valley concentration of this IL-17 binding molecule of about 8 μ g/ml or about 17 μ g/ml.

68. a method for the treatment of excessive risk RA patient comprises:

A) use the IL-17 binding molecule to patient that these needs are arranged during induction scheme, this induction scheme provides the average maximal plasma concentration (C of this IL-17 binding molecule of about 401 μ g/ml _Max); And

B) thereafter, use the IL-17 binding molecule to this patient during Concept of Maintenance, this Concept of Maintenance provides:

I) about 9.4 μ g/ml are to the average steady state valley concentration of this IL-17 binding molecule of about 31 μ g/ml; And/or

Ii) about 314mg * day/L average A UC τ to the stable state of about 1256mg * day/L.

69. one kind is used for the treatment of psoriasic IL-17 binding molecule, it is characterized in that this IL-17 binding molecule:

A) use to this patient during induction scheme, this induction scheme provides the average maximal plasma concentration (C of this IL-17 binding molecule of about 401 μ g/ml _Max); And

70. as the described method of claim 68 or the described purposes of claim 69, wherein this Concept of Maintenance provides about 9.4 μ g/ml average steady state valley concentration to this IL-17 binding molecule of about 17.3 μ g/ml.

71. as the described method of claim 70 or purposes, wherein this Concept of Maintenance provides the average steady state valley concentration of this IL-17 binding molecule of about 9.4 μ g/ml or about 17.3 μ g/ml.

72. as claim 63 or 68 described methods or claim 64 or 69 described purposes, wherein this induction scheme comprises that intravenous is used this IL-17 binding molecule week about.

73. as claim 63 or 68 described methods or claim 64 or 69 described purposes, wherein this Concept of Maintenance comprises every month this IL-17 binding molecule of subcutaneous administration.

74. a test kit, it comprises:

A) pharmaceutical composition, this pharmaceutical composition comprise the IL-17 antagonist of the rheumatoid arthritis (RA) that is used for the treatment of the patient; And

B) description from this pharmaceutical composition to this patient that how use is described, wherein this patient is characterised in that: i) be RF+, ACPA+ or RF+ and ACPA+ the two; And ii) have high CRP level, high ESR or have high CRP level simultaneously and high ESR the two.

75.IL-17 antagonist is in the purposes of medicine for the preparation for the treatment of RA, prerequisite is that this patient is based on following standard and treats through selecting:

A) be RF+, ACPA+ or RF+ and ACPA+ the two; And

76.IL-17 antagonist is for the preparation of the purposes in treatment patient's the medicine of RA, this patient is characterised in that:

A) be RF+, ACPA+ or RF+ and ACPA+ the two; And

B) have high CRP level, high ESR or have high CRP level simultaneously and high ESR the two, wherein this medicine through preparation comprising container, this IL-17 antagonist that each container has a capacity with allow send per unit dosage at least about 75mg to about 150mg IL-17 antagonist.

77.IL-17 antagonist is for the preparation of the purposes in treatment patient's the medicine of RA, this patient is characterised in that:

A) be RF+, ACPA+ or RF+ and ACPA+ the two; And

B) have high CRP level, high ESR or have high CRP level simultaneously and high ESR the two, wherein this medicine through the preparation to comprise container, each container has this IL-17 antagonist of capacity and sends per unit dosage at least about 10mg/kg to allow.

78.IL-17 antagonist is for the preparation of the purposes in treatment patient's the medicine of RA, this patient is characterised in that:

A) be RF+, ACPA+ or RF+ and ACPA+ the two; And

B) have high CRP level, high ESR or have high CRP level simultaneously and high ESR the two, wherein this medicine through the preparation to allow the dosage of sending the about 10mg/kg of per unit dosage through intravenous.

79.IL-17 antagonist is for the preparation of the purposes in treatment patient's the medicine of RA, this patient is characterised in that:

A) be RF+, ACPA+ or RF+ and ACPA+ the two; And

B) have high CRP level, high ESR or have high CRP level simultaneously and high ESR the two, wherein this medicine through preparation to allow the extremely dosage of about 150mg IL-17 antagonist of the about 75mg of subcutaneous delivery per unit dosage.

80. a testing in vitro method of selecting the patient to carry out the RA treatment, this method comprises definite:

I. this patient whether be RF+, ACPA+ or RF+ and ACPA+ the two; And

Ii. this patient whether have high CRP level, high ESR or have high CRP level simultaneously and high ESR the two.

81. as the described testing in vitro method of claim 80, wherein this patient has improved treatment to following scheme and replys:

A) use the IL-17 antagonist of the dosage of three doses of about 10mg/kg to this patient, first dosage is to send during the 0th week, and second dosage is to send during the 2nd week, and the 3rd dosage is to send during the 4th week; And

B) begin during the 8th week thereafter, every month twice, every month, per two months or every three months are used about 75mg to this IL-17 antagonist of about 150mg to this patient.

But 82. producing method about the information of the patient's that suffers from RA transmission form, it comprises:

A) the following project of analysis patient sample:

I) rheumatoid factor (RF), anti-citrulline protein antibodies (ACPA) or RF and ACPA; And

Ii) C-reactive protein (CRP), erythrosedimentation speed (ESR) or CRP and ESR the two; And b) but the result of step a) is the information of ready-made transmission form.

83. as claim 1-29,63,65-68, each described method of 70-73,80-82, the described test kit of claim 74, claim 30-58,61,64-67, each described purposes of 69-73,75-79, each described pharmaceutical composition of claim 59-61, the described scheme of claim 62, wherein this IL-17 antagonist is IL-17 binding molecule or IL-17 receptors bind molecule.

84. as the described method of claim 83, purposes, pharmaceutical composition, test kit or scheme, wherein this IL-17 binding molecule or IL-17 receptors bind molecule are to be selected from following IL-17 binding molecule:

A) Su Jin monoclonal antibody;

B) in conjunction with the IL-17 antibody of the epi-position of IL-17, this epi-position comprises Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129;

C) in conjunction with the IL-17 antibody of the epi-position of IL-17, this epi-position comprises Tyr43, Tyr44, Arg46, Ala79, Asp80;

D) in conjunction with the IL-17 antibody of epi-position of the IL-17 homodimer with two ripe IL-17 protein chains, this epi-position comprises Tyr43, Tyr44, Arg46, Ala79, an Asp80 on Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 and another chain on the chain;

E) in conjunction with the IL-17 antibody of epi-position of the IL-17 homodimer with two ripe IL-17 protein chains, this epi-position comprises Tyr43, Tyr44, Arg46, Ala79, an Asp80 on Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 and another chain on the chain, wherein this IL-17 binding molecule has the KD of about 100pM to 200pM, and wherein this IL-17 binding molecule has the half-life in the body in about 4 weeks; And

F) IL-17 antibody, it comprises and is selected from following antibody:

I) comprise the immunoglobulin heavy chain variable domain (V of the aminoacid sequence shown in the SEQ ID NO:8 _H);

Immunoglobulin light chain variable domain (the V that ii) comprises the aminoacid sequence shown in the SEQ ID NO:10 _L);

The immunoglobulin V that iii) comprises the aminoacid sequence shown in this SEQ ID NO:8 _HDomain and comprise the immunoglobulin V of the aminoacid sequence shown in this SEQ ID NO:10 _LDomain;

The immunoglobulin V that iv) comprises the hypervariable region shown in SEQ ID NO:1, SEQ ID NO:2 and the SEQ ID NO:3 _HDomain;

The immunoglobulin V that v) comprises the hypervariable region shown in SEQ ID NO:4, SEQ ID NO:5 and the SEQ ID NO:6 _LDomain;

The immunoglobulin V that vi) comprises the hypervariable region shown in SEQ ID NO:11, SEQ ID NO:12 and the SEQ ID NO:13 _HDomain;

The immunoglobulin V that vii) comprises the hypervariable region shown in SEQ ID NO:1, SEQ ID NO:2 and the SEQ ID NO:3 _HDomain and comprise SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 shown in the immunoglobulin V of hypervariable region _LDomain; And

The immunoglobulin V that viii) comprises the hypervariable region shown in SEQ ID NO:11, SEQ ID NO:12 and the SEQ ID NO:13 _HDomain and comprise SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 shown in the immunoglobulin V of hypervariable region _LDomain.

85. as the described method of claim 84, purposes, pharmaceutical composition, test kit or scheme, wherein this IL-17 binding molecule is the Su Jin monoclonal antibody.